Selective heterocyclic sphingosine 1 phosphate receptor modulators

ABSTRACT

Compounds that selectively modulate the sphingosine 1 phosphate receptor are provided including compounds which modulate subtype 1 of the S1P receptor. Methods of chiral synthesis of such compounds are provided. Uses, methods of treatment or prevention and methods of preparing inventive compositions including inventive compounds are provided in connection with the treatment or prevention of diseases, malconditions, and disorders for which modulation of the sphingosine 1 phosphate receptor is medically indicated.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/946,828 filed Nov. 15, 2010 (allowed), which claims the priority ofU.S. Application No. 61/261,295 filed Nov. 13, 2009 and U.S. ApplicationNo. 61/262,474 filed Nov. 18, 2009, the disclosures of which areincorporated herein in their entireties.

FIELD OF THE INVENTION

The invention relates to compounds which are agonists of the sphingosine1-phosphate receptor subtype 1, methods of their synthesis and methodsof their therapeutic and/or prophylactic use.

BACKGROUND

The S1P₁/EDG₁ receptor is a G-protein coupled receptor (GPCR) and is amember of the endothelial cell differentiation gene (EDG) receptorfamily. Endogenous ligands for EDG receptors include lysophospholipids,such as sphingosine-1-phosphate (S1P). Like all GPCRs, ligation of thereceptor propagates second messenger signals via activation ofG-proteins (alpha, beta and gamma).

Development of small molecule S1P₁ agonists and antagonists has providedinsight into some physiological roles of the S1P₁/S1P-receptor signalingsystem. Agonism of the S1P₁ receptor perturbs lymphocyte trafficking,sequestering them in lymph nodes and other secondary lymphoid tissue.This leads to rapid and reversible lymphopenia, and is probably due toreceptor ligation on both lymphatic endothelial cells and lymphocytesthemselves (Rosen et al, Immunol. Rev., 195:160-177, 2003). A clinicallyvaluable consequence of lymphocyte sequestration is exclusion of themfrom sights of inflammation and/or auto-immune reactivity in peripheraltissues.

Agonism of S1P₁ has also been reported to promote survival ofoligodendrocyte progenitors (Miron et al, Ann. Neurol., 63:61-71, 2008).This activity, in conjunction with lymphocyte sequestration would beuseful in treating inflammatory and autoimmune conditions of the centralnervous system.

SUMMARY OF THE INVENTION

The present invention is directed to heterocyclic compounds adapted toact as agonists of SIP receptor subtype 1, S1P₁; methods of preparationand methods of use, such as in treatment of a malcondition mediated byS1P₁ activation, or when activation of S1P₁ is medically indicated.

Certain embodiments of the present invention comprise a compound havingthe structure of Formula (I) or a pharmaceutically acceptable salt,ester, prodrug, homolog, tautomer, stereoisomer, or hydrate, or solvatethereof:

A dashed line signifies that a single bond or a double bond can bepresent, provided that there are two double bonds and three single bondsin the ring comprising A¹, A², and A³. A¹, A², and A³ each independentlycan be C or S or N; provided that one of A¹, A², and A³ is S.

R¹ can be di-substituted phenyl or di-substituted pyridinyl where thephenyl and pyridinyl substituents can each be independently any of halo,nitro, cyano, perfluromethyl, fluorinated methyl, and C₁₋₄-alkoxy. WhenR¹ is di-substituted phenyl, such phenyl is para-substituted withC₁₋₄-alkoxy.

R² can be

wherein a wavy line indicates a point of attachment.

X can be —NR′R″ or —OR′″;

R′ can be H, C₁₋₄ alkyl, n-hydroxy C₁₋₄ alkyl, —SO₂—R³, or —CO—R³. R″can be H, —SO₂—R⁵, C₁₋₄ alkyl optionally substituted with 1 or more R⁴,or a ring moiety optionally substituted with R⁶ wherein such ring moietyis piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl,pyrrolidinyl, imidazolyl, or phenyl. R′″ can be H, C₁₋₄ alkyl, or—CO—R³. R′ and R″ taken together with the nitrogen atom to which theyare bound can form a 4, 5, or 6 membered saturated heterocyclic ringcontaining 0 or 1 additional heteroatoms where such additionalheteroatom is O or N wherein such heterocycle is optionally singly ormultiply substituted with substituents independently selected from thegroup consisting of —OH, oxo, —NH₂, n-hydroxy-C₁₋₄ alkyl, —COOH,—(CH₂)_(m)—COOH, —(CH₂)_(m)—COOR³, —N(R³R³), and —(CH₂)_(m)—CO—N(R⁷R⁷).Each R³ can be independently C₁₋₄ alkyl or H. Each R⁴ can beindependently H, halo, OH, oxo, ═NH, NH₂, —COOH, F, —N(R⁷R⁷), —SO₂—R³,—SO₂—N(R⁷R⁷), —N(R³)—SO₂—R³, —COOR³, —OCO—R³, —CO—N(R⁷R⁷), —N(R³)—COR³,C₁₋₃ alkyl, C₁₋₃ alkoxy, and a ring moiety optionally substituted withR⁶ wherein such ring moiety is piperazinyl, piperidinyl, morpholinyl,pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl,cyclobutinyl, or phenyl. Each R⁵ can be independently R⁴, C₁₋₄ alkyl,C₃₋₆ cycloalkyl, or C₁₋₄ alkyl optionally substituted with 1 or more R⁴.Each R⁶ can be independently halo, OH, —NH₂, —NHR³, —N(R³R³), —COOH,—COOR³, —NHCO—R³. Each R⁷ can be independently C₁₋₄ alkyl or H, or twoR⁷ taken together with the nitrogen atom to which they are bound canform a 4, 5, or 6 membered saturated heterocyclic ring containing 0 or 1additional heteroatoms where such additional heteroatom is O or Nwherein such heterocycle can be optionally substituted with —OH, —NH₂,—N(R³R³), n-hydroxy C₁₋₄ alkyl, —(CH₂)_(m)—COOH, —(CH₂)_(m)—COOR³. Eachm can be independently 0, 1, 2, or 3.

In certain embodiments, a pharmaceutical composition comprising acompound of the invention and a suitable excipient is provided.

In certain embodiments a method of use of an inventive compoundcomprising preparation of a medicament is provided.

In certain combinations a pharmaceutical combination comprising acompound of the invention and a second medicament is provided. Invarious embodiments the second medicament is medically indicated for thetreatment of multiple sclerosis, transplant rejection, acute respiratorydistress syndrome or adult respiratory distress syndrome.

In certain embodiments, a method of activation or agonism of asphingosine-1-phosphate receptor subtype 1 comprising contacting thereceptor subtype 1 with a compound of claim 1 is provided. In variousembodiments, the compound of claim 1 activates or agonizes thesphingosine-1-phosphate receptor subtype 1 to a greater degree than thecompound activates or agonizes a sphingosin-1-phosphate receptor subtype3.

In certain embodiments a method of treatment of a malcondition in apatient for which activation or agonism of an S1P₁ receptor is medicallyindicated, is provided. In various embodiment, selective activation oragonism of an S1P₁ receptor, such as with respect to an S1P₃ receptor,is medically indicated. In various embodiments, the malconditioncomprises multiple sclerosis, transplant rejection, or acute respiratorydistress syndrome.

In certain embodiments, a method is provided for chiral synthesis ofcertain compounds including compounds of the invention. In certain otherembodiments the invention provides certain intermediate compoundsassociated with such methods of chiral synthesis.

DETAILED DESCRIPTION OF THE INVENTION

Certain embodiments of the present invention comprise a compound havingthe structure of Formula (I) or a pharmaceutically acceptable salt,ester, prodrug, homolog, tautomer, stereoisomer, or hydrate, or solvatethereof:

A dashed line signifies that a single bond or a double bond can bepresent, provided that there are two double bonds and three single bondsin the ring comprising A¹, A², and A³. A¹, A², and A³ each independentlycan be C or S or N; provided that one of A¹, A², and A³ is S.

R¹ can be di-substituted phenyl or di-substituted pyridinyl where thephenyl and pyridinyl substituents can each be independently any of halo,nitro, cyano, perfluromethyl, fluorinated methyl, and C₁₋₄-alkoxy. WhenR¹ is di-substituted phenyl, such phenyl is para-substituted withC₁₋₄-alkoxy.

R² can be

wherein a wavy line indicates a point of attachment.

X can be —NR′R″ or —OR′″;

R′ can be H, C₁₋₄ alkyl, n-hydroxy C₁₋₄ alkyl, —SO₂—R³, or —CO—R³. R″can be H, —SO₂—R⁵, C₁₋₄ alkyl optionally substituted with 1 or more R⁴,or a ring moiety optionally substituted with R⁶ wherein such ring moietyis piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl,pyrrolidinyl, imidazolyl, or phenyl. R′″ can be H, C₁₋₄ alkyl, or—CO—R³. R′ and R″ taken together with the nitrogen atom to which theyare bound can form a 4, 5, or 6 membered saturated heterocyclic ringcontaining 0 or 1 additional heteroatoms where such additionalheteroatom is O or N wherein such heterocycle is optionally singly ormultiply substituted with substituents independently selected from thegroup consisting of —OH, oxo, —NH₂, n-hydroxy-C₁₋₄ alkyl, —COOH,—(CH₂)_(m)—COOH, —(CH₂)_(m)—COOR³, —N(R³R³), and —(CH₂)_(m)—CO—N(R⁷R⁷).Each R³ can be independently C₁₋₄ alkyl or H. Each R⁴ can beindependently H, halo, OH, oxo, ═NH, NH₂, —COOH, F, —NHR³, —N(R⁷R⁷),—SO₂—R³, —SO₂—N(R⁷R⁷), —N(R³)—SO₂—R³, —COOR³, —OCO—R³, —CO—N(R⁷R⁷),—N(R³)—COR³, C₁₋₃ alkyl, C₁₋₃ alkoxy, and a ring moiety optionallysubstituted with R⁶ wherein such ring moiety is piperazinyl,piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl,benzimidazolyl, azetidinyl, cyclobutinyl, or phenyl. Each R⁵ can beindependently R⁴, C₁₋₄ alkyl, C₃₋₆ cycloalkyl, or C₁₋₄ alkyl optionallysubstituted with 1 or more R⁴. Each R⁶ can be independently halo, OH,—NH₂, —NHR³, —N(R³R³), —COOH, —COOR³, —NHCO—R³. Each R⁷ can beindependently C₁₋₄ alkyl or H, or two R⁷ taken together with thenitrogen atom to which they are bound can form a 4, 5, or 6 memberedsaturated heterocyclic ring containing 0 or 1 additional heteroatomswhere such additional heteroatom is O or N wherein such heterocycle canbe optionally substituted with —OH, —NH₂, —N(R³R³), n-hydroxy C₁₋₄alkyl, —(CH₂)_(m)—COOH, —(CH₂)_(m)—COOR³. Each m can be independently 0,1, 2, or 3.

In certain embodiments, the compounds of the invention have thestructure of a specific of Formula I or a pharmaceutically acceptablesalt, ester, prodrug, homolog, hydrate or solvate thereof. In certainembodiments the invention provides compounds which are substantiallyenantiomerically pure. In certain such embodiments, the compounds areenantiomerically pure with respect to a chiral carbon on an indanyl ortetrahydronaphthalenyl moiety.

In certain embodiments the invention provides compounds which have anEC₅₀ as an agonist of the wild type S1P receptor subtype 1 which is atleast ten times smaller than the EC₅₀ of such compound as an agonist ofa mutant S1P receptor subtype 1 having a single mutation with respect towild type S1P receptor subtype 1 such that the 101^(st) amino acidresidue is changed from asparagine to alanine.

In certain embodiments the invention provides compounds which have anEC₅₀ as an agonist of the wild type S1P receptor subtype 1 which is atleast twenty times smaller than the EC₅₀ of such compound as an agonistof a mutant S1P receptor subtype 1 having a single mutation with respectto wild type S1P receptor subtype 1 such that the 101^(st) amino acidresidue is changed from asparagine to alanine.

In certain embodiments the invention provides compounds which have atherapeutic index of at least 5 as measured in rats following 5 or 14days of dosing of rats with the compound where the therapeutic index iscalculated as a ratio of (i) the highest dose of such compound whichachieves less than or equal to a ten percent increase in the ratio oflung to terminal body weight at the conclusion of such 5 or 14 days ofdosing, to (ii) the dose of such compound achieving 50% lymphopenia inrats. In certain embodiments, such therapeutic index is at least 10 andin certain embodiments the therapeutic index is at least 20. In certainembodiments, the therapeutic index for a compound is at least five timesgreater than the therapeutic index for the enantiomer of such compound.

In certain embodiments the invention provides compounds which have atherapeutic index of at least 5 as measured in rats following 5 or 14days of dosing of rats with the compound where the therapeutic index iscalculated as a ratio of (i) the highest dose of such compound whichachieves less than or equal to a ten percent increase in the ratio oflung to terminal body weight at the conclusion of such 5 or 14 days ofdosing, to (ii) the dose of such compound achieving 50% lymphopenia inrats. In certain embodiments, such therapeutic index is at least 10 andin certain embodiments the therapeutic index is at least 20. In certainembodiments, the therapeutic index for a compound is greater than thetherapeutic index for the enantiomer of such compound. In certainembodiments, the therapeutic index for a compound is at least 150% ofthe therapeutic index for the enantiomer of such compound.

In certain embodiments the invention provides compounds where thestructure of Formula I is selected from the group consisting of formulasa-i through a-x:

In certain embodiments the invention provides compounds where A¹ is S,in other embodiments the invention provides compounds where A² is S andin other embodiments the invention provides compounds where A³ is S. Incertain embodiments A¹ is N and A² is C or N; in certain suchembodiments A² is C and in others A² is N.

In certain embodiments the invention provides compounds where R¹ is

R³ is C₂₋₄ alkyl; and Y is —CN, —Cl, —O—R³, or —CF₃. In certain suchembodiments R³ is isopropyl or ethyl. In certain embodiments Y is —CN or—O—C₂H₅.

In certain embodiments the invention provides compounds where R² is

In certain of such embodiments the invention provides compounds where R²is

In other embodiments the invention provides compounds where R² is

In certain of such embodiments the compound is substantiallyenantiomerically pure.

In certain embodiments the invention provides compounds where Y is Cl,in other embodiments the invention provides compounds where Y is CF₃ andin other embodiments the invention provides compounds where Y is CN.

In certain embodiments the invention provides compounds where X is—NR′R″, in other embodiments the invention provides compounds where X is—OR′″. In certain embodiments the invention provides compounds where Xis —OR′″. In certain embodiments the invention provides compounds whereX is —OH and in other embodiments the invention provides compounds whereX is —OCO—R³.

In certain embodiments the invention provides compounds where R³ is C₁₋₃alkyl; in other embodiments the invention provides compounds where R′ isH.

In certain embodiments the invention provides compounds where R′ is—COR³; in other embodiments the invention provides compounds where R′ isSO₂—R³. In certain embodiments the invention provides compounds where R″is H.

In certain embodiments the invention provides compounds where R″ is—SO₂—R⁵; in other embodiments the invention provides compounds where R″is C₁₋₄ alkyl where the C₁₋₄ alkyl is optionally substituted with 1 ormore substituents defined by R⁴. In certain embodiments the inventionprovides compounds where R″ is —(CR^(a)R^(b))_(n)—R⁴ and each R^(a) andeach R^(b) can be independently any of H, hydroxyl and methyl or whereR^(a) and R^(b) are bound to the same carbon they can be taken togetherto form oxo (i.e. with the carbon to which they are bound forming acarbonyl moiety). In certain such embodiments n can be 0, 1, 2, or 3 andin certain embodiments n is 2. In certain such embodiments R² can be—OH, —NH₂, —NHR³, —N(R⁷R⁷), or —COOH.

In certain embodiments the invention provides compounds where R⁵ is C₁₋₄alkyl optionally substituted with 1 or more R⁴. In certain embodimentsthe invention provides compounds where R⁴ is OH; in other embodimentsthe invention provides compounds where R⁴ is C₁₋₃ alkoxy. In certainembodiments the invention provides compounds where R⁵ is (CH₂)₂—OR³.

In certain embodiments the invention provides compounds where Y is CNand X is —NH—SO₂—R⁵. In certain embodiments the invention providescompounds where R⁵ is —C₂H₅—N((R⁷R⁷) or —CH₂—CO—N(R⁷R⁷). In certainembodiments the invention provides compounds where Y is CN and X is—NH—CO—N(R⁷R⁷).

In certain embodiments X is —NH₂ and in certain of such embodiments Y isCN.

In certain embodiments the invention provides one or more of compounds1-227:

or any pharmaceutically acceptable salt, tautomer, stereoisomer,solvate, hydrate, or prodrug thereof. In certain of such embodiments,the invention provides a compound selected from compounds 43, 46, 47,56, 58, 166, 172, and 186 or any pharmaceutically acceptable salt,ester, tautomer, stereoisomer, solvate, hydrate, homolog, or prodrugthereof. In certain of such embodiments, the invention provides compound43, 46, or 166 or any pharmaceutically acceptable salt, ester, tautomer,solvate, hydrate, homolog, or prodrug thereof.

In certain embodiments, an invention compound of Formula I is providedwherein the compound has at least one chiral center and is substantiallyenantiomerically pure.

In other embodiments, a pharmaceutical composition comprising aninvention compound of Formula I and a suitable excipient is provided.

In other embodiments, a pharmaceutical combination comprising aninvention compound and a second medicament is provided. In still otherembodiments, a pharmaceutical combination comprising an inventioncompound and a second medicament is provided wherein the secondmedicament is medically indicated for the treatment of multiplesclerosis, transplant rejection, or adult respiratory distress syndrome.

In certain embodiments, a method of use of an invention compound forpreparation of a medicament is provided.

In certain embodiments a method of activation or agonism of asphingosine-1-phosphate receptor subtype 1 by contacting the receptorsubtype 1 with an effective amount of an invention compound. In furtherembodiments, a method of activation or agonism of asphingosine-1-phosphate receptor subtype 1 by contacting the receptorsubtype 1 with an effective amount of an invention compound is provided,wherein the compound activates or agonizes the sphingosine-1-phosphatereceptor subtype 1 to a greater extent than the compound activates oragonizes a sphingosine-1-phosphate receptor subtype 3. In furtherembodiments, a method of activation or agonism of asphingosine-1-phosphate receptor subtype 1 by contacting the receptorsubtype 1 with an effective amount of an invention compound is provided,wherein the sphingosine-1-phosphate receptor subtype 1 is disposedwithin a living mammal.

In certain embodiments, a method is provided for treatment of amalcondition in a patient for which activation or agonism of ansphingosine-1-phosphate receptor subtype 1 is medically indicated, byadministering an effective amount of an invention compound to thepatient at a frequency and for a duration of time sufficient to providea beneficial effect to the patient. In further embodiments, a method isprovided for treatment of a malcondition in a patient for whichactivation or agonism of an sphingosine-1-phosphate receptor subtype 1is medically indicated, by administering an effective amount of aninvention compound to the patient at a frequency and for a duration oftime sufficient to provide a beneficial effect to the patient, whereinselective activation or agonism of an S1P subtype 1 receptor withrespect to other subtypes of S1P receptor is medically indicated. In yetfurther embodiments, a method is provided for treatment of amalcondition in a patient for which activation or agonism of ansphingosine-1-phosphate receptor subtype 1 is medically indicated, byadministering an effective amount of an invention compound to thepatient at a frequency and for a duration of time sufficient to providea beneficial effect to the patient, wherein the malcondition comprisesrejection of transplanted organs or tissue; graft-versus-host diseasesbrought about by transplantation; autoimmune syndromes includingrheumatoid arthritis; acute respiratory distress syndrome; adultrespiratory distress syndrome; influenza; cancer; systemicerythematosus; Hashimoto's thyroiditis; lymphocytic thyroiditis;multiple sclerosis; myasthenia gravis; type I and II diabetes; uveitis;posterior uveitis; uveitis associated with Behcet's disease;uveomeningitis syndrome; allergic encephalomyelitis; chronic allograftvasculopathy; post-infectious autoimmune diseases including rheumaticfever and post-infectious glomerulonephritis; inflammatory andhyperproliferative skin diseases; cutaneous manifestations ofimmunologically-mediated disorders; psoriasis; atopic dermatitis;osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeicdermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysisbullosa; urticaria; angioedema; vasculitis; erythema; cutaneouseosinophilia; acne; alopecia areata; keratoconjunctivitis; vernalconjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialiscorneae; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerativekeratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Haradasyndrome; sarcoidosis; pollen allergies; reversible obstructive airwaydisease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsicasthma; dust asthma; chronic or inveterate asthma; late asthma andairway hyper-responsiveness; bronchitis; gastric ulcers; ischemic boweldiseases; inflammatory bowel diseases; necrotizing enterocolitis;intestinal lesions associated with thermal burns; celiac diseases;proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease;ulcerative colitis; vascular damage caused by ischemic diseases andthrombosis; atherosclerosis; fatty heart; myocarditis; cardiacinfarction; arteriosclerosis; aortitis syndrome; cachexia due to viraldisease; vascular thrombosis; migraine; rhinitis; eczema; interstitialnephritis; IgA-induced nephropathy; Goodpasture's syndrome;hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis;glomerulonephritis; multiple myositis; Guillain-Barre syndrome;Meniere's disease; polyneuritis; multiple neuritis; mononeuritis;radiculopathy; hyperthyroidism; Basedow's disease; thyrotoxicosis; purered cell aplasia; aplastic anemia; hypoplastic anemia; idiopathicthrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis;pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis;sarcoidosis; fibroid lung; idiopathic interstitial pneumonia;dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergicsensitivity; cutaneous T cell lymphoma; polyarteritis nodosa;Huntington's chorea; Sydenham's chorea; myocardosis; scleroderma;Wegener's granuloma; Sjogren's syndrome; adiposis; eosinophilicfascitis; lesions of gingiva, periodontium, alveolar bone, substantiaossea dentis; male pattern alopecia or alopecia senilis; musculardystrophy; pyoderma; Sezary's syndrome; chronic adrenal insufficiency;Addison's disease; ischemia-reperfusion injury of organs which occursupon preservation; endotoxin shock; pseudomembranous colitis; colitiscaused by drug or radiation; ischemic acute renal insufficiency; chronicrenal insufficiency; lung cancer; malignancy of lymphoid origin; acuteor chronic lymphocytic; leukemias; lymphoma; psoriasis; inflammatorylung injury, pulmonary emphysema; cataracta; siderosis; retinitispigmentosa; senile macular degeneration; vitreal scarring; inflammatoryeye disease; corneal alkali burn; dermatitis erythema; ballousdermatitis; cement dermatitis; gingivitis; periodontitis; sepsis;pancreatitis; carcinogenesis; metastasis of carcinoma; hypobaropathy;autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis;partial liver resection; acute liver necrosis; cirrhosis; alcoholiccirrhosis; hepatic failure; fulminant hepatic failure; late-onsethepatic failure; “acute-on-chronic” liver failure. In yet furtherembodiments, the malcondition is one or more of rejection oftransplanted organs or tissue; graft-versus-host diseases brought aboutby transplantation; autoimmune syndromes including rheumatoid arthritis,multiple sclerosis, myasthenia gravis; pollen allergies; type Idiabetes; prevention of psoriasis; Crohn's disease; ulcerative colitis,acute respiratory distress syndrome; adult respiratory distresssyndrome; influenza; post-infectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis; and metastasisof carcinoma. In yet further embodiments the malcondition is one ofinfluenza, ulcerative colitis, multiple sclerosis, transplant rejection,acute respiratory distress syndrome or adult respiratory distresssyndrome.

In certain embodiments, methods are provided for use of an inventioncompound for preparation of a medicament adapted for treatment of adisorder or a malcondition wherein activation or inhibition of asphingosine-1-phosphate receptor subtype 1 is medically indicated.

In certain embodiments the invention provides a method for the chiralsynthesis of a compound comprising an indane moiety having a chiralcarbon in the five-membered ring of the indane moiety where the compoundis enantiomerically enriched with respect to the chiral carbon. In suchembodiments, the method of the invention provides the steps of

(i) providing a compound comprising an indane moiety where the ringcarbon of the five-membered ring of the indane moiety where chiralsubstitution is desired is oxo substituted at such carbon, and wherein acarbon of the phenyl ring is halo substituted;

(ii) reacting such compound with a chiral reagent selected from thegroup consisting of a Corey Bakshita Shibata-oxazaborolidine and achiral sulfinamide of the form RS(═O)NH₂ where R is selected from thegroup consisting of t-butyl, branched C₂₋₆ alkyl and C₃₋₈ cycloalkyl;and

(iii) forming the chiral center at the indane moiety carbon previouslybound to the oxo group by either reacting such compound with a suitablereducing agent along with the chiral reagent in step (ii) or reactingthe result of the reaction of such compound with a suitable reducingagent.

In certain embodiments R is t-butyl, sec-butyl, isopropyl, cyclopropyl,adamantyl, C₃₋₆ branched alkyl, or optionally bridged C₃₋₈ cycloalkyl.In certain of such embodiments the chiral reagent is the Corey BakshitaShibata-oxazaborolidine and the compound comprising an indane moiety isenantiomerically enriched with respect to a carbon-oxygen bond on a ringcarbon of the five-membered ring of the indane moiety. In certain ofsuch embodiments a suitable reducing reagent includes a borohydride suchas BH₃-DMS or NaBH₄.

In further embodiments, the chiral reagent is(R)-(−)-(2)-methyl-CBS-oxazaborolidine or(S)-(−)-(2)-methyl-CBS-oxazaborolidine.

In certain of such embodiments the compound comprising an indane moietyprovided in step (i) is contacted with the chiral reagent to form instep (ii) Formula VI-R or VI-S:

wherein Z is Cl, Br or I.

In certain embodiments the method further comprises the step ofprotecting the hydroxy group of Formula VI-R or VI-S by treating FormulaVI-R or VI-S with a protecting agent to form Formula VIa-R or VIa-S:

wherein PG is a protecting group.

Protecting groups can render chemical functionality inert to specificreaction conditions and can be appended to and removed from suchfunctionality in a molecule without substantially damaging the remainderof the molecule. Practitioners in the art would be familiar withsuitable protecting groups for use in the synthetic methods of theinvention. See, e.g., Greene and Wuts, Protective Groups in OrganicSynthesis, 2^(nd) ed., John Wiley & Sons, New York, 1991. In certainembodiments such protecting agent is t-butyldimethylsilyl chloride(TBSC1).

In certain embodiments the method further comprises the step of reactingFormula VIa-R or VIa-S with boronic acid or bis(pinacolato)diboron toform a boronic acid or boronate ester of Formula VIb-R or VIb-S:

In certain embodiments the chiral reagent is RS(═O)NH₂ and the compoundcomprising an indane moiety is enantiomerically enriched with respect toa carbon-nitrogen bond on a ring carbon of the five-membered ring of theindane moiety. In further embodiments the chiral reagent ist-Bu-S(═O)NH₂.

In certain embodiments the compound comprising an indane moiety providedin step (i) is contacted with the chiral reagent to form in step (ii)Formula VII-R or VII-S:

wherein Z is Cl, Br or I.

In certain embodiments a compound of Formula VIII-R or VIII-S is formedin step (iii):

In certain embodiments the method further comprises the step ofcontacting Formula VIII-R or VIII-S with 1,4-dioxane in the presence ofan acid to form Formula VIb-R or VIb-S or Formula IX-R or IX-S:

In certain embodiments the method further comprises the step ofprotecting the amino group by treating Formula IX-R or IX-S with aprotecting agent to form Formula IXa-R or IXa-S:

In certain of such embodiments the protecting agent isdi-tert-butyldicarbonate.

In certain embodiments the method further comprises the step of reactingFormula IXa-R or IXa-S with boronic acid or bis(pinacolato)diboron toform a boronic acid or boronate ester of Formula IXb-R or IXb-S:

In certain embodiments the method further comprises the step of reactingFormula VIb-R, Formula VIb-S, Formula IXb-R or Formula IXb-S withFormula XI:

to form Formula XII-R or XII-S:

wherein each A¹ and each A² is independently N, or CH; R¹ isdi-substituted phenyl or di-substituted pyridinyl where the phenyl andpyridinyl substituents are each independently selected from the groupconsisting of halo, nitro, cyano, perfluromethyl, fluorinated methyl,and C₁₋₄-alkoxy; provided that if R¹ is di-substituted phenyl, suchphenyl is para-substituted with C₁₋₄-alkoxy; and X is NH or O.

In further embodiments R¹ is di-substituted phenyl where the phenylsubstituents are F and Y, wherein Y is —CN, —Cl, or —CF₃. In stillfurther embodiment Y is —CN.

In certain embodiments the method further comprises the step of reactingFormula XII-R or XII-S with iPrOH in the presence of NaOiPr to fromFormula XIII-R or XIII-S:

In certain embodiments the method further comprises the step ofdeprotecting the hydroxyl group wherein X is O, or the amino groupwherein X is NH, by treating Formula XIII-R or XIII-S with adeprotecting agent. In further embodiments the method further comprisesthe step of converting the deprotected amino group to a secondary amine.

In certain embodiments A¹ is N and A² is N. In certain of suchembodiments Formula XI is prepared following the process comprising thestep of

a) treating a di-substituted benzaldehyde with potassium phosphatemonobasic to form a di-substituted benzoic acid;

b) contacting the di-substituted benzoic acid with H₂NNHCSNH₂ to form anamino-1,3-4-thiadizole having a di-substituted phenyl group substitutedon the thiadiazole moiety; and

c) treating the amino-1,3-4-thiadizole in step b) with a mixture ofcopper bromide and isoamylnitrite.

In certain embodiments A¹ is N and A² is CH. In certain of suchembodiments Formula XI is prepared following the process comprising thestep of

a) contacting 2-bromothiazole with a (di-substituted phenyl)boronic acidto form a 2-(di-substituted phenyl)thiazole; and

b) treating the 2-(di-substituted phenyl)thiazole with NBS.

In certain embodiments A¹ is CH and A² is N. In certain of suchembodiments Formula XI is prepared following the process comprising thestep of

a) contacting 5-(tributylstannyl)thiazole with an iodobenzene having twoother substituents to form a 5-(di-substituted phenyl)thiazole; and

b) treating the 2-(di-substituted phenyl)thiazole with NBS.

In certain embodiments, the method of the invention provides the stepsof

(i) providing the compound

and

(ii) reacting such compound with a chiral reagent selected from thegroup consisting of a Corey Bakshita Shibata-oxazaborolidine and achiral sulfinamide of the form RS(═O)NH₂ where R is a bulky group [e.g.t-butyl, branched alkyl or cycloalkyl]; and

(iii) forming a chiral center at the indane moiety carbon previouslybound to the oxo group by either reacting such compound with a suitablereducing agent along with the chiral reagent in step (ii) or reactingthe result of the reaction of such compound with a suitable reducingagent.

In certain of such embodiments, the chiral reagent is a Corey BakshitaShibata-oxazaborolidine and X is —OR′″. In further embodiments, thechiral reagent is (R)-(−)-(2)-methyl-CBS-oxazaborolidine or(S)-(−)-(2)-methyl-CBS-oxazaborolidine.

In certain of such embodiments the chiral reagent is RS(═O)NH₂ where Ris branched alkyl or cycloalkyl and X is —NR′ R″. In further suchembodiments, the chiral reagent is t-Bu-S(═O)NH₂.

In certain of such embodiments a suitable reducing reagent includes aborohydride such as BH₃-DMS or NaBH₄.

Additional steps for the preparation of such compounds can be adaptedfrom the synthetic methods disclosed herein including recrystallizationand other processes for purification.

In certain of such embodiments the invention provides a method ofsynthesizing a chiral compound of the invention by (i) providing acompound comprising an indane moiety where the ring carbon of thefive-membered ring of the indane moiety where chiral substitution isdesired is oxo substituted at such carbon; (ii) reacting such compoundwith a chiral reagent selected from the group consisting of a CoreyBakshita Shibata-oxazaborolidine and a chiral sulfinamide of the formRS(═O)NH₂ where R is a bulky group [e.g. t-butyl or other branched alkylor cycloalkyl]; and (iii) forming a chiral center at the indane moietycarbon previously bound to the oxo group by either reacting suchcompound with a suitable reducing agent along with the chiral reagent instep (ii) or reacting the result of the reaction of such compound with asuitable reducing agent.

Additional steps for the preparation of such compounds can be adaptedfrom the synthetic methods disclosed herein including recrystallizationand other processes for purification.

In certain of such embodiments the invention provides a method ofsynthesizing a chiral compound of the invention by (i) providing acompound comprising an indane moiety where the ring carbon of thefive-membered ring of the indane moiety where chiral substitution isdesired is oxo substituted at such carbon; (ii) reacting such compoundwith a chiral reagent selected from the group consisting of a CoreyBakshita Shibata-oxazaborolidine and a chiral sulfinamide of the formRS(═O)NH₂ where R is a bulky group [e.g. t-butyl or other branched alkylor cycloalkyl]; and (iii) forming a chiral center at the indane moietycarbon previously bound to the oxo group by either reacting suchcompound with a suitable reducing agent along with the chiral reagent instep (ii) or reacting the result of the reaction of such compound with asuitable reducing agent.

In certain of such embodiments, the invention provides a method forchiral synthesis of a chiral compound comprising an indane moiety havinga chiral carbon in the five-membered ring of the indane moiety or achiral compound comprising an oxadiazole-indane moiety having a chiralcarbon in the five-membered ring of the indane moiety where the chiralcompound has an enantiomeric enrichment of at least 75%, 85%, 90%, 95%,98%, or 99%.

In certain of such embodiments, the invention provides a method forsynthesis of a chiral compound of the invention having an enantiomericenrichment of at least 75%, 85%, 90%, 95%, 98%, or 99%.

In certain embodiments, a method for the synthesis of a compoundcomprising an indane moiety having a chiral carbon in the five-memberedring of the indane moiety where the compound is enantiomericallyenriched with respect to the chiral carbon is provided. In certainembodiments, a method comprising a step of providing a compound of thestructures described herein is provided.

As used in the specification and the appended claims, the singular forms“a,” “an” and “the” include plural referents unless the context clearlydictates otherwise.

As used herein, “individual” (as in the subject of the treatment) meansboth mammals and non-mammals. Mammals include, for example, humans;non-human primates, e.g. apes and monkeys; cattle; horses; sheep; andgoats. Non-mammals include, for example, fish and birds.

The term “S1P₁” as used herein refers to subtype 1 of asphingosine-1-phosphate receptor, while other sphingosine-1-phosphatereceptor subtypes are referred to in a corresponding manner, forexample, sphingosine-1-phosphate receptor subtype 3 is referred to as“S1P₃”

A “receptor”, as is well known in the art, is a biomolecular entityusually comprising a protein that specifically binds a structural classof ligands or a single native ligand in a living organism, the bindingof which causes the receptor to transduce the binding signal intoanother kind of biological action, such as signaling a cell that abinding event has occurred, which causes the cell to alter its functionin some manner. An example of transduction is receptor binding of aligand causing alteration of the activity of a “G-protein” in thecytoplasm of a living cell. Any molecule, naturally occurring or not,that binds to a receptor and activates it for signal transduction, isreferred to as an “agonist” or “activator.” Any molecule, naturallyoccurring or not, that binds to a receptor, but does not cause signaltransduction to occur, and which can block the binding of an agonist andits consequent signal transduction, is referred to as an “antagonist.”

An “S1P₁ compound” or “S1P₁ agonist” or “S1P₁ activator” or “S1P₁inhibitor” or “S1P₁ antagonist” as the terms are used herein refer tocompounds that interact in some way with the SIP receptor subtype 1.They can be agonist or activators, or they can be antagonists orinhibitors. An “S1P₁ compound” of the invention can be selective foraction on subtype 1 of the S1P receptor family; for example a compoundof the invention can act at a lower concentration on subtype 1 of theSIP receptor family than on other subtypes of the SIP receptor family;more specifically, an “S1P₁ compound” of the invention can selectivelyact on subtype 1 receptors compared to its action on subtype 3, or“S1P₃” receptors.

In certain embodiments, compounds of the invention are orthostaticagonists. In certain other embodiments, compounds of the invention areallosteric agonists. Receptor agonists may be classified as eitherorthosteric or allosteric. An orthosteric agonist binds to a site in thereceptor that significantly overlaps with the binding of the naturalligand and replicates the key interactions of the natural ligand withthe receptor. An orthosteric agonist will activate the receptor by amolecular mechanism similar to that of the natural ligand, will becompetitive for the natural ligand, and will be competitivelyantagonized by pharmacological agents that are competitive antagonistsfor the natural ligand. An allosteric agonist binds to a site in thereceptor that makes some significant interactions that are partly orwholly non-overlapping with the natural ligand. Allosteric agonists aretrue agonists and not allosteric potentiators. Consequently, theyactivate receptor signaling alone and without a requirement for asub-maximal concentration of the natural ligand. Allosteric agonists maybe identified when an antagonist known to be competitive for theorthosteric ligand shows non-competitive antagonism. The allostericagonist site can also be mapped by receptor mutagenesis. Theintroduction of single point mutations in receptors that retain receptoractivation by allosteric agonist, while diminishing or abolishingsignaling induced by orthosteric agonist or vice versa provide formalevidence for differences in binding interactions. Orthosteric agonistsmay destabilize GPCR structure and conformation, while allostericagonists may either stabilize or destabilize GPCR structure andconformation. Allosteric agonists, by virtue of their differentinteractions with receptor, may be pharmaceutically useful because theallosteric site may confer additional opportunities for agonist potencyand selectivity within a related family of receptor subtypes that sharea similar orthosteric ligand. In addition, the allosteric site mayrequire very different physical and chemical properties of an agonistcompared to the orthosteric ligand. These chemico-physical properties,which include hydrophobicity, aromaticity, charge distribution andsolubility may also provide advantages in generating agonists of varyingpharmacokinetic, oral bioavailability, distributional and metabolismprofiles that facilitate the development of effective pharmaceuticalsubstances.

“Substantially” as the term is used herein means completely or almostcompletely; for example, a composition that is “substantially free” of acomponent either has none of the component or contains such a traceamount that any relevant functional property of the composition isunaffected by the presence of the trace amount, or a compound is“substantially pure” is there are only negligible traces of impuritiespresent.

Substantially enantiomerically pure means a level of enantiomericenrichment of one enantiomer with respect to the other enantiomer of atleast 90%, 95%, 98%, 99%, 99.5% or 99.9%.

“Treating” or “treatment” within the meaning herein refers to analleviation of symptoms associated with a disorder or disease, orinhibition of further progression or worsening of those symptoms, orprevention or prophylaxis of the disease or disorder.

The expression “effective amount”, when used to describe use of acompound of the invention in providing therapy to a patient sufferingfrom a disorder or malcondition mediated by a sphingosine-1-phosphatereceptor of subtype 1 refers to the amount of a compound of theinvention that is effective to bind to as an agonist or as an antagonista S1P₁ receptor in the individual's tissues, wherein the S1P₁ isimplicated in the disorder, wherein such binding occurs to an extentsufficient to produce a beneficial therapeutic effect on the patient.Similarly, as used herein, an “effective amount” or a “therapeuticallyeffective amount” of a compound of the invention refers to an amount ofthe compound that alleviates, in whole or in part, symptoms associatedwith the disorder or condition, or halts or slows further progression orworsening of those symptoms, or prevents or provides prophylaxis for thedisorder or condition. In particular, a “therapeutically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired therapeutic result by acting asan agonist of sphingosine-1-phosphate receptor subtype 1 (S1P₁)activity. A therapeutically effective amount is also one in which anytoxic or detrimental effects of compounds of the invention areoutweighed by the therapeutically beneficial effects. For example, inthe context of treating a malcondition mediated by activation of S1P₁, atherapeutically effective amount of an S1P₁ agonist of the invention isan amount sufficient to control the malcondition, to mitigate theprogress of the malcondition, or to relieve the symptoms of themalcondition. Examples of malconditions that can be so treated includemultiple sclerosis, transplant rejection, adult respiratory distresssyndrome.

Diseases, disorders and conditions which may be treated by compounds ofthe invention include rejection of transplanted organs or tissue;graft-versus-host diseases brought about by transplantation; autoimmunesyndromes including rheumatoid arthritis; acute respiratory distresssyndrome; adult respiratory distress syndrome; influenza; cancer;systemic erythematosus; Hashimoto's thyroiditis; lymphocyticthyroiditis; multiple sclerosis; myasthenia gravis; type I and IIdiabetes; uveitis; posterior uveitis; uveitis associated with Behcet'sdisease; uveomeningitis syndrome; allergic encephalomyelitis; chronicallograft vasculopathy; post-infectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis; inflammatory andhyperproliferative skin diseases; cutaneous manifestations ofimmunologically-mediated disorders; psoriasis; atopic dermatitis;osteomyelitis; contact dermatitis; eczematous dermatitis; seborrhoeicdermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysisbullosa; urticaria; angioedema; vasculitis; erythema; cutaneouseosinophilia; acne; alopecia areata; keratoconjunctivitis; vernalconjunctivitis; keratitis; herpetic keratitis; dystrophia epithelialiscorneae; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerativekeratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Haradasyndrome; sarcoidosis; pollen allergies; reversible obstructive airwaydisease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsicasthma; dust asthma; chronic or inveterate asthma; late asthma andairway hyper-responsiveness; bronchitis; gastric ulcers; ischemic boweldiseases; inflammatory bowel diseases; necrotizing enterocolitis;intestinal lesions associated with thermal burns; celiac diseases;proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease;ulcerative colitis; vascular damage caused by ischemic diseases andthrombosis; atherosclerosis; fatty heart; myocarditis; cardiacinfarction; arteriosclerosis; aortitis syndrome; cachexia due to viraldisease; vascular thrombosis; migraine; rhinitis; eczema; interstitialnephritis; IgA-induced nephropathy; Goodpasture's syndrome;hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis;glomerulonephritis; multiple myositis; Guillain-Barre syndrome;Meniere's disease; polyneuritis; multiple neuritis; mononeuritis;radiculopathy; hyperthyroidism; Basedow's disease; thyrotoxicosis; purered cell aplasia; aplastic anemia; hypoplastic anemia; idiopathicthrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis;pernicious anemia; megaloblastic anemia; anerythroplasia; osteoporosis;sarcoidosis; fibroid lung; idiopathic interstitial pneumonia;dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergicsensitivity; cutaneous T cell lymphoma; polyarteritis nodosa;Huntington's chorea; Sydenham's chorea; myocardosis; scleroderma;Wegener's granuloma; Sjogren's syndrome; adiposis; eosinophilicfascitis; lesions of gingiva, periodontium, alveolar bone, substantiaossea dentis; male pattern alopecia or alopecia senilis; musculardystrophy; pyoderma; Sezary's syndrome; chronic adrenal insufficiency;Addison's disease; ischemia-reperfusion injury of organs which occursupon preservation; endotoxin shock; pseudomembranous colitis; colitiscaused by drug or radiation; ischemic acute renal insufficiency; chronicrenal insufficiency; lung cancer; malignancy of lymphoid origin; acuteor chronic lymphocytic; leukemias; lymphoma; psoriasis; inflammatorylung injury, pulmonary emphysema; cataracta; siderosis; retinitispigmentosa; senile macular degeneration; vitreal scarring; inflammatoryeye disease; corneal alkali burn; dermatitis erythema; ballousdermatitis; cement dermatitis; gingivitis; periodontitis; sepsis;pancreatitis; carcinogenesis; metastasis of carcinoma; hypobaropathy;autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis;partial liver resection; acute liver necrosis; cirrhosis; alcoholiccirrhosis; hepatic failure; fulminant hepatic failure; late-onsethepatic failure; “acute-on-chronic” liver failure. Particularlypreferred diseases and conditions which may be treated with compounds ofthe invention comprise the group consisting of rejection of transplantedorgans or tissue; graft-versus-host diseases brought about bytransplantation; autoimmune syndromes including rheumatoid arthritis,multiple sclerosis, myasthenia gravis; pollen allergies; type Idiabetes; prevention of psoriasis; Crohn's disease; ulcerative colitis,acute respiratory distress syndrome; adult respiratory distresssyndrome; influenza; post-infectious autoimmune diseases includingrheumatic fever and post-infectious glomerulonephritis; and metastasisof carcinoma.

Furthermore, compounds of Formula I-R or I—S are also useful, incombination with one or several immunosuppressant agents, for thetreatment of diseases, disorders and conditions associated with anactivated immune system and selected from the list as above-mentioned.According to a preferred embodiment of the invention, saidimmunosuppressant agent is selected from the group comprising orconsisting of cyclosporin, daclizumab, basiliximab, everolimus,tacrolimus (FK506), azathiopirene, leflunomide, 15-deoxyspergualin, orother immunosuppressant drugs

All chiral, diastereomeric, racemic forms of a structure are intended,unless a particular stereochemistry or isomeric form is specificallyindicated. Compounds used in the present invention can include enrichedor resolved optical isomers at any or all asymmetric atoms as areapparent from the depictions, at any degree of enrichment. Both racemicand diastereomeric mixtures, as well as the individual optical isomerscan be synthesized so as to be substantially free of their enantiomericor diastereomeric partners, and these are all within the scope ofcertain embodiments of the invention.

The isomers resulting from the presence of a chiral center comprise apair of non-superimposable isomers that are called “enantiomers.” Singleenantiomers of a pure compound are optically active, i.e., they arecapable of rotating the plane of plane polarized light. Singleenantiomers are designated according to the Cahn-Ingold-Prelog system.Once the priority ranking of the four groups is determined, the moleculeis oriented so that the lowest ranking group is pointed away from theviewer. Then, if the descending rank order of the other groups proceedsclockwise, the molecule is designated (R) and if the descending rank ofthe other groups proceeds counterclockwise, the molecule is designated(S). In the examples, the Cahn-Ingold-Prelog ranking is A>B>C>D. Thelowest ranking atom, D is oriented away from the viewer.

“Isolated optical isomer” means a compound which has been substantiallypurified from the corresponding optical isomer(s) of the same formula.Preferably, the isolated isomer is at least about 80%, more preferablyat least 90% pure, even more preferably at least 98% pure, mostpreferably at least about 99% pure, by weight.

Rotational Isomerism

It is understood that due to chemical properties (i.e., resonancelending some double bond character to the C—N bond) of restrictedrotation about the amide bond linkage (as illustrated below) it ispossible to observe separate rotamer species and even, under somecircumstances, to isolate such species, example shown below. It isfurther understood that certain structural elements, including stericbulk or substituents on the amide nitrogen, may enhance the stability ofa rotamer to the extent that a compound may be isolated as, and existindefinitely, as a single stable rotamer. The present inventiontherefore includes any possible stable rotamers of compounds of theinvention which are biologically active in the treatment of a disease,disorder or condition for which a compound of the invention may beeffective as described herein.

Regioisomerism

The preferred compounds of the present invention have a particularspatial arrangement of substituents on the aromatic rings, which isrelated to the structure activity relationship demonstrated by thecompound class. Often such substitution arrangement is denoted by anumbering system; however, numbering systems are often not consistentbetween different ring systems. In six-membered aromatic systems, thespatial arrangements are specified by the common nomenclature “para” for1,4-substitution, “meta” for 1,3-substitution and “ortho” for1,2-substitution as shown below.

All structures encompassed within a claim are “chemically feasible”, bywhich is meant that the structure depicted by any combination orsubcombination of optional substituents meant to be recited by the claimis physically capable of existence with at least some stability as canbe determined by the laws of structural chemistry and byexperimentation. Structures that are not chemically feasible are notwithin a claimed set of compounds.

In general, “substituted” refers to an organic group as defined hereinin which one or more bonds to a hydrogen atom contained therein arereplaced by one or more bonds to a non-hydrogen atom such as, but notlimited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groupssuch as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxygroups, oxo(carbonyl) groups, carboxyl groups including carboxylicacids, carboxylates, and carboxylate esters; a sulfur atom in groupssuch as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups,sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atomin groups such as amines, hydroxylamines, nitriles, nitro groups,N-oxides, hydrazides, azides, and enamines; and other heteroatoms invarious other groups. Non-limiting examples of substituents that can bebonded to a substituted carbon (or other) atom include F, Cl, Br, I,OR′, OC(O)N(R′)₂, CN, CF₃, OCF₃, R′, O, S, C(O), S(O), methylenedioxy,ethylenedioxy, N(R′)₂, SR′, SOR′, SO₂R′, SO₂N(R)₂, SO₃R′, C(O)R′,C(O)C(O)R′, C(O)CH₂C(O)R′, C(S)R′, C(O)OR′, OC(O)R′, C(O)N(R′)₂,OC(O)N(R′)₂, C(S)N(R)₂, (CH₂)₀₋₂NHC(O)R′, (CH₂)₀₋₂N(R)N(R)₂,N(R′)N(R′)C(O)R′, N(R′)N(R′)C(O)OR′, N(R′)N(R′)CON(R′)₂, N(R′)SO₂R′,N(R)SO₂N(R′)₂, N(R)C(O)OR′, N(R′)C(O)R′, N(R′)C(S)R′, N(R′)C(O)N(R′)₂,N(R′)C(S)N(R′)₂, N(COR′)COR′, N(OR′)R′, C(═NH)N(R′)₂, C(O)N(OR′)R′, orC(═NOR′)R′ wherein R′ can be hydrogen or a carbon-based moiety, andwherein the carbon-based moiety can itself be further substituted.

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groupsas well as other substituted groups also include groups in which one ormore bonds to a hydrogen atom are replaced by one or more bonds,including double or triple bonds, to a carbon atom, or to a heteroatomsuch as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester,amide, imide, urethane, and urea groups; and nitrogen in imines,hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.The substituents of the substituted groups can further be substitutedwith alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and alkynyl groups asdefined herein, which can themselves be further substituted. Forexample, an C₁₋₄ alkyl group can be substituted with an amide, and theamide can further be substituted with another C₁₋₄ alkyl, which canfurther be substituted.

Substituted ring groups such as substituted aryl, heterocyclyl andheteroaryl groups also include rings and fused ring systems in which abond to a hydrogen atom is replaced with a bond to a carbon atom.Therefore, substituted aryl, heterocyclyl and heteroaryl groups can alsobe substituted with alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, andalkynyl groups as defined herein, which can themselves be furthersubstituted.

The term “heteroatoms” as used herein refers to non-carbon andnon-hydrogen atoms, capable of forming covalent bonds with carbon, andis not otherwise limited. Typical heteroatoms are N, O, and S. Whensulfur (S) is referred to, it is understood that the sulfur can be inany of the oxidation states in which it is found, thus includingsulfoxides (R—S(O)—R′) and sulfones (R—S(O)₂—R′), unless the oxidationstate is specified; thus, the term “sulfone” encompasses only thesulfone form of sulfur; the term “sulfide” encompasses only the sulfide(R—S—R′) form of sulfur. When the phrases such as “heteroatoms selectedfrom the group consisting of O, NH, NR′ and S,” or “[variable] is O, S .. . ” are used, they are understood to encompass all of the sulfide,sulfoxide and sulfone oxidation states of sulfur.

Alkyl groups include straight chain and branched alkyl groups andcycloalkyl groups having from 1 to about 20 carbon atoms (C₁₋₂₀ alkyl),and typically from 1 to 12 carbons (C₁₋₁₂ alkyl) or, in someembodiments, from 1 to 8 carbon atoms (C₁₋₈ alkyl) or, in someembodiments, from 1 to 4 carbon atoms (C₁₋₄ alkyl) or, in someembodiments, from 1 to 3 carbon atoms (C₁₋₃ alkyl). Examples of straightchain alkyl groups include, but are not limited to methyl, ethyl,n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.Examples of branched alkyl groups include, but are not limited to,isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and2,2-dimethylpropyl groups. Representative substituted alkyl groups canbe substituted one or more times with any of the groups listed above,for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups. The group “n-hydroxy C₁₋₄ alkyl” represents a C₁₋₄ alkylsubstituted with a terminal hydroxy group.

Cycloalkyl groups are alkyl groups forming a ring structure, which canbe substituted or unsubstituted. Examples of cycloalkyl include, but arenot limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkylgroup has 3 to 8 ring members, whereas in other embodiments the numberof ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkylgroups further include polycyclic cycloalkyl groups such as, but notlimited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, andcarenyl groups, and fused rings such as, but not limited to, decalinyl,and the like. Cycloalkyl groups also include rings that are substitutedwith straight or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2,2-, 2,3-,2,4-2,5- or 2,6-disubstituted cyclohexyl groups or mono-, di- ortri-substituted norbornyl or cycloheptyl groups, which can besubstituted with, for example, amino, hydroxy, cyano, carboxy, nitro,thio, alkoxy, and halogen groups.

The terms “carbocyclic” and “carbocycle” denote a ring structure whereinthe atoms of the ring are carbon. In some embodiments, the carbocyclehas 3 to 8 ring members, whereas in other embodiments the number of ringcarbon atoms is 4, 5, 6, or 7. Unless specifically indicated to thecontrary, the carbocyclic ring can be substituted with as many as Nsubstituents wherein N is the size of the carbocyclic ring with forexample, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, andhalogen groups.

(Cycloalkyl)alkyl groups, also denoted cycloalkylalkyl, are alkyl groupsas defined above in which a hydrogen or carbon bond of the alkyl groupis replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkylgroups as defined above, except that at least one double bond existsbetween two carbon atoms. Thus, alkenyl groups have from 2 to about 20carbon atoms, and typically from 2 to 12 carbons or, in someembodiments, from 2 to 8 carbon atoms. Examples include, but are notlimited to —CH═CH(CH₃), —CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃),—C(CH₂CH₃)═CH₂, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl,butadienyl, pentadienyl, and hexadienyl among others.

The term “cycloalkenyl” alone or in combination denotes a cyclic alkenylgroup wherein at least one double bond is present in the ring structure.Cycloalkenyl groups include cycloalkyl groups having at least one doublebond between two adjacent carbon atoms. Thus for example, cycloalkenylgroups include but are not limited to cyclohexenyl, cyclopentenyl, andcyclohexadienyl groups.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of the alkyl group is replaced with a bond to acycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, exceptthat at least one triple bond exists between two carbon atoms. Thus,alkynyl groups have from 2 to about 20 carbon atoms, and typically from2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.Examples include, but are not limited to —C≡CH, —C≡C(CH₃), —C≡C(CH₂CH₃),—CH₂C≡CH, —CH₂C≡C(CH₃), and —CH₂C≡C(CH₂CH₃), among others.

Aryl groups are cyclic aromatic hydrocarbons that do not containheteroatoms. Thus aryl groups include, but are not limited to, phenyl,azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl,triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl,anthracenyl, and naphthyl groups. In some embodiments, aryl groupscontain 6-14 carbons in the ring portions of the groups. The phrase“aryl groups” includes groups containing fused rings, such as fusedaromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, andthe like), and also includes substituted aryl groups that have othergroups, including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, or alkoxy groups, bonded to one of the ring atoms.Representative substituted aryl groups can be mono-substituted orsubstituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-,or 6-substituted phenyl or naphthyl groups, which can be substitutedwith groups including but not limited to those listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen orcarbon bond of an alkyl group is replaced with a bond to an aryl groupas defined above. Representative aralkyl groups include benzyl andphenylethyl groups and fused (cycloalkylaryl)alkyl groups such as4-ethyl-indanyl. The aryl moiety or the alkyl moiety or both areoptionally substituted with other groups, including but not limited toalkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxygroups. Aralkenyl group are alkenyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to anaryl group as defined above.

Heterocyclyl groups include aromatic and non-aromatic ring compounds(heterocyclic rings) containing 3 or more ring members, of which one ormore is a heteroatom such as, but not limited to, N, O, S, or P. In someembodiments, heterocyclyl groups include 3 to 20 ring members, whereasother such groups have 3 to 15 ring members. At least one ring containsa heteroatom, but every ring in a polycyclic system need not contain aheteroatom. For example, a dioxolanyl ring and a benzdioxolanyl ringsystem (methylenedioxyphenyl ring system) are both heterocyclyl groupswithin the meaning herein. A heterocyclyl group designated as aC₂-heterocyclyl can be a 5-membered ring with two carbon atoms and threeheteroatoms, a 6-membered ring with two carbon atoms and fourheteroatoms and so forth. Likewise a C₄-heterocyclyl can be a 5-memberedring with one heteroatom, a 6-membered ring with two heteroatoms, and soforth. The number of carbon atoms plus the number of heteroatoms sums upto equal the total number of ring atoms. A saturated heterocyclic ringrefers to a heterocyclic ring containing no unsaturated carbon atoms.

The phrase “heterocyclyl group” includes fused ring species includingthose having fused aromatic and non-aromatic groups. The phrase alsoincludes polycyclic ring systems containing a heteroatom such as, butnot limited to, quinuclidyl and also includes heterocyclyl groups thathave substituents, including but not limited to alkyl, halo, amino,hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, bonded to one ofthe ring members. A heterocyclyl group as defined herein can be aheteroaryl group or a partially or completely saturated cyclic groupincluding at least one ring heteroatom. Heterocyclyl groups include, butare not limited to, pyrrolidinyl, furanyl, tetrahydrofuranyl,dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl,thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl,dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.Heterocyclyl groups can be substituted. Representative substitutedheterocyclyl groups can be mono-substituted or substituted more thanonce, including but not limited to, rings containing at least oneheteroatom which are mono, di, tri, tetra, penta, hexa, orhigher-substituted with substituents such as those listed above,including but not limited to alkyl, halo, amino, hydroxy, cyano,carboxy, nitro, thio, and alkoxy groups.

Heteroaryl groups are aromatic ring compounds containing 5 or more ringmembers, of which, one or more is a heteroatom such as, but not limitedto, N, O, and S. A heteroaryl group designated as a C₂-heteroaryl can bea 5-membered ring with two carbon atoms and three heteroatoms, a6-membered ring with two carbon atoms and four heteroatoms and so forth.Likewise a C₄-heteroaryl can be a 5-membered ring with one heteroatom, a6-membered ring with two heteroatoms, and so forth. The number of carbonatoms plus the number of heteroatoms sums up to equal the total numberof ring atoms. Heteroaryl groups include, but are not limited to, groupssuch as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl,isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl,benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl,azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl,imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl,xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl,tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, andquinazolinyl groups. The terms “heteroaryl” and “heteroaryl groups”include fused ring compounds such as wherein at least one ring, but notnecessarily all rings, are aromatic, including tetrahydroquinolinyl,tetrahydroisoquinolinyl, indolyl and 2,3-dihydro indolyl. The term alsoincludes heteroaryl groups that have other groups bonded to one of thering members, including but not limited to alkyl, halo, amino, hydroxy,cyano, carboxy, nitro, thio, or alkoxy groups. Representativesubstituted heteroaryl groups can be substituted one or more times withgroups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are notlimited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl),N-hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl,anthracenyl (1-anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl(2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl), indolyl, oxadiazolyl,isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl,acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl),imidazolyl (1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl),triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-oxazolyl),thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl,3-pyridyl, 4-pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl,5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl,4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl(1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl,6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo[b]furanyl(2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl),2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl),3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro-benzo[b]furanyl),5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl),7-(2,3-dihydro-benzo[b]furanyl), benzo[b]thiophenyl(2-benzo[b]thiophenyl, 3-benzo[b]thiophenyl, 4-benzo[b]thiophenyl,5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl),2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro-benzo[b]thiophenyl),3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro-benzo[b]thiophenyl),5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl),7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole(1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl,7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl,4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl,8-benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl),benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl,5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl(1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl),5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl,5H-dibenz[b,f]azepine-2-yl, 5H-dibenz[b,f]azepine-3-yl,5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5-yl),10,11-dihydro-5H-dibenz[b,f]azepine(10,11-dihydro-5H-dibenz[b,f]azepine-1-yl,10,11-dihydro-5H-dibenz[b,f]azepine-2-yl,10,11-dihydro-5H-dibenz[b,f]azepine-3-yl,10,11-dihydro-5H-dibenz[b,f]azepine-4-yl,10,11-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheterocyclyl group as defined above. Representative heterocyclyl alkylgroups include, but are not limited to, furan-2-yl methyl, furan-3-ylmethyl, pyridine-2-yl methyl (α-picolyl), pyridine-3-yl methyl(β-picolyl), pyridine-4-yl methyl (γ-picolyl), tetrahydrofuran-2-ylethyl, and indol-2-yl propyl. Heterocyclylalkyl groups can besubstituted on the heterocyclyl moiety, the alkyl moiety, or both.

Heteroarylalkyl groups are alkyl groups as defined above in which ahydrogen or carbon bond of an alkyl group is replaced with a bond to aheteroaryl group as defined above. Heteroarylalkyl groups can besubstituted on the heteroaryl moiety, the alkyl moiety, or both.

By a “ring system” as the term is used herein is meant a moietycomprising one, two, three or more rings, which can be substituted withnon-ring groups or with other ring systems, or both, which can be fullysaturated, partially unsaturated, fully unsaturated, or aromatic, andwhen the ring system includes more than a single ring, the rings can befused, bridging, or spirocyclic. By “spirocyclic” is meant the class ofstructures wherein two rings are fused at a single tetrahedral carbonatom, as is well known in the art.

A “monocyclic, bicyclic or polycyclic, aromatic or partially aromaticring” as the term is used herein refers to a ring system including anunsaturated ring possessing 4n+2 pi electrons, or a partially reduced(hydrogenated) form thereof. The aromatic or partially aromatic ring caninclude additional fused, bridged, or spiro rings that are notthemselves aromatic or partially aromatic. For example, naphthalene andtetrahydronaphthalene are both a “monocyclic, bicyclic or polycyclic,aromatic or partially aromatic ring” within the meaning herein. Also,for example, a benzo-[2.2.2]-bicyclooctane is also a “monocyclic,bicyclic or polycyclic, aromatic or partially aromatic ring” within themeaning herein, containing a phenyl ring fused to a bridged bicyclicsystem. A fully saturated ring has no double bonds therein, and iscarbocyclic or heterocyclic depending on the presence of heteroatomswithin the meaning herein.

The term “alkoxy” refers to an oxygen atom connected to an alkyl group,including a cycloalkyl group, as are defined above. Examples of linearalkoxy groups include but are not limited to methoxy, ethoxy, n-propoxy,n-butoxy, n-pentyloxy, n-hexyloxy, and the like. Examples of branchedalkoxy include but are not limited to isopropoxy, sec-butoxy,tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclicalkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, and the like.

The terms “aryloxy” and “arylalkoxy” refer to, respectively, an arylgroup bonded to an oxygen atom and an aralkyl group bonded to the oxygenatom at the alkyl moiety. Examples include but are not limited tophenoxy, naphthyloxy, and benzyloxy.

An “acyl” group as the term is used herein refers to a group containinga carbonyl moiety wherein the group is bonded via the carbonyl carbonatom. The carbonyl carbon atom is also bonded to another carbon atom,which can be part of an alkyl, aryl, aralkyl cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl,heteroarylalkyl group or the like. In the special case wherein thecarbonyl carbon atom is bonded to a hydrogen, the group is a “formyl”group, an acyl group as the term is defined herein. An acyl group caninclude 0 to about 12-20 additional carbon atoms bonded to the carbonylgroup. An acyl group can include double or triple bonds within themeaning herein. An acryloyl group is an example of an acyl group. Anacyl group can also include heteroatoms within the meaning here. Anicotinoyl group (pyridyl-3-carbonyl) group is an example of an acylgroup within the meaning herein. Other examples include acetyl, benzoyl,phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and thelike. When the group containing the carbon atom that is bonded to thecarbonyl carbon atom contains a halogen, the group is termed a“haloacyl” group. An example is a trifluoroacetyl group.

The term “amine” includes primary, secondary, and tertiary amineshaving, e.g., the formula N(group)₃ wherein each group can independentlybe H or non-H, such as alkyl, aryl, and the like. Amines include but arenot limited to RNH₂, for example, alkylamines, arylamines,alkylarylamines; R₂NH wherein each R is independently selected, such asdialkylamines, diarylamines, aralkylamines, heterocyclylamines and thelike; and R₃N wherein each R is independently selected, such astrialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, andthe like. The term “amine” also includes ammonium ions as used herein.

An “amino” group is a substituent of the form —NH₂, —NHR, —NR₂, —NR₃ ⁺,wherein each R is independently selected, and protonated forms of each.Accordingly, any compound substituted with an amino group can be viewedas an amine.

An “ammonium” ion includes the unsubstituted ammonium ion NH₄ ⁺, butunless otherwise specified, it also includes any protonated orquaternarized forms of amines. Thus, trimethylammonium hydrochloride andtetramethylammonium chloride are both ammonium ions, and amines, withinthe meaning herein.

The term “amide” (or “amido”) includes C- and N-amide groups, i.e.,—C(O)NR′R″, and —NR′C(O)R″ groups, respectively. The R′ and R″ of theC-amide may join together to form a heterocyclic ring with the nitrogenatom. Amide groups therefore include but are not limited to carbamoylgroups (—C(O)NH₂) and formamide groups (—NHC(O)H). A “carboxamido” groupis a group of the formula C(O)NR₂, wherein R can be H, alkyl, aryl, etc.

The term “urethane” (or “carbamyl”) includes N- and O-urethane groups,i.e., —NRC(O)OR and —OC(O)NR₂ groups, respectively.

The term “sulfonamide” (or “sulfonamido”) includes S- and N-sulfonamidegroups, i.e., —SO₂NR₂ and —NRSO₂R groups, respectively. Sulfonamidegroups therefore include but are not limited to sulfamoyl groups(—SO₂NH₂).

The term “amidine” or “amidino” includes groups of the formula—C(NR)NR₂. Typically, an amidino group is —C(NH)NH₂.

The term “guanidine” or “guanidino” includes groups of the formula—NRC(NR)NR₂. Typically, a guanidino group is —NHC(NH)NH₂.

“Halo,” “halogen,” and “halide” include fluorine, chlorine, bromine andiodine.

The terms “comprising,” “including,” “having,” “composed of,” areopen-ended terms as used herein, and do not preclude the existence ofadditional elements or components. In a claim element, use of the forms“comprising,” “including,” “having,” or “composed of” means thatwhatever element is comprised, had, included, or composes is notnecessarily the only element encompassed by the subject of the clausethat contains that word.

A “salt” as is well known in the art includes an organic compound suchas a carboxylic acid, a sulfonic acid, or an amine, in ionic form, incombination with a counterion. For example, acids in their anionic formcan form salts with cations such as metal cations, for example sodium,potassium, and the like; with ammonium salts such as NH₄ ⁺ or thecations of various amines, including tetraalkyl ammonium salts such astetramethylammonium and alkyl ammonium salts such as tromethamine salts,or other cations such as trimethylsulfonium, and the like. A“pharmaceutically acceptable” or “pharmacologically acceptable” salt isa salt formed from an ion that has been approved for human consumptionand is generally non-toxic, such as a chloride salt or a sodium salt. A“zwitterion” is an internal salt such as can be formed in a moleculethat has at least two ionizable groups, one forming an anion and theother a cation, which serve to balance each other. For example, aminoacids such as glycine can exist in a zwitterionic form. A “zwitterion”is a salt within the meaning herein. The compounds of the presentinvention may take the form of salts. The term “salts” embraces additionsalts of free acids or free bases which are compounds of the invention.Salts can be “pharmaceutically-acceptable salts.” The term“pharmaceutically-acceptable salt” refers to salts which possesstoxicity profiles within a range that affords utility in pharmaceuticalapplications. Pharmaceutically unacceptable salts may nonethelesspossess properties such as high crystallinity, which have utility in thepractice of the present invention, such as for example utility inprocess of synthesis, purification or formulation of compounds of theinvention.

Suitable pharmaceutically-acceptable acid addition salts may be preparedfrom an inorganic acid or from an organic acid. Examples of inorganicacids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic,sulfuric, and phosphoric acids. Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid. Examples ofpharmaceutically unacceptable acid addition salts include, for example,perchlorates and tetrafluoroborates.

Suitable pharmaceutically acceptable base addition salts of compounds ofthe invention include, for example, metallic salts including alkalimetal, alkaline earth metal and transition metal salts such as, forexample, calcium, magnesium, potassium, sodium and zinc salts.Pharmaceutically acceptable base addition salts also include organicsalts made from basic amines such as, for example,N,N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples ofpharmaceutically unacceptable base addition salts include lithium saltsand cyanate salts. Although pharmaceutically unacceptable salts are notgenerally useful as medicaments, such salts may be useful, for exampleas intermediates in the synthesis of compounds, for example in theirpurification by recrystallization. All of these salts may be prepared byconventional means from the corresponding compound by reacting, forexample, the appropriate acid or base with the compound. The term“pharmaceutically acceptable salts” refers to nontoxic inorganic ororganic acid and/or base addition salts, see, for example, Lit et al.,Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217,incorporated by reference herein

Nonlimiting examples of potential salts of this invention include butare not limited to hydrochloride, citrate, glycolate, fumarate, malate,tartrate, mesylate, esylate, cinnamate, isethionate, sulfate, phosphate,diphosphate, nitrate, hydrobromide, hydroiodide, succinate, formate,acetate, dichloroacetate, lactate, p-toluenesulfonate, pamitate,pidolate, pamoate, salicylate, 4-aminosalicylate, benzoate, 4-acetamidobenzoate, glutamate, aspartate, glycolate, adipate, alginate, ascorbate,besylate, camphorate, camphorsulfonate, camsylate, caprate, caproate,cyclamate, laurylsulfate, edisylate, gentisate, galactarate, gluceptate,gluconate, glucuronate, oxoglutarate, hippurate, lactobionate, malonate,maleate, mandalate, napsylate, napadisylate, oxalate, oleate, sebacate,stearate, succinate, thiocyanate, undecylenate, and xinafoate.

A “hydrate” is a compound that exists in a composition with watermolecules. The composition can include water in stoichiometicquantities, such as a monohydrate or a dihydrate, or can include waterin random amounts. As the term is used herein a “hydrate” refers to asolid form, i.e., a compound in water solution, while it may behydrated, is not a hydrate as the term is used herein.

A “homolog” of a compound of the invention is a compound having one ormore atoms of the compound replaced by an isotope of such atom. Forexample, homologs include compounds with deuterium in place of somehydrogen atoms of the compound such as compounds of the invention inwhich the methyl groups of the isopropoxy moiety of Formulas I-R and I-Sare fully or partially deuterated (e.g., (D₃C)₂C—O—). Isotopicsubstitutions which may be made in the formation of homologs of theinvention include non-radioactive (stable) atoms such as deuterium andcarbon 13, as well as radioactive (unstable) atoms such as tritium,carbon 14, iodine 123, iodine 125, etc.

A “solvate” is a similar composition except that a solvent other thatwater replaces the water. For example, methanol or ethanol can form an“alcoholate”, which can again be stoichiometic or non-stoichiometric. Asthe term is used herein a “solvate” refers to a solid form, i.e., acompound in solution in a solvent, while it may be solvated, is not asolvate as the term is used herein.

A “prodrug” as is well known in the art is a substance that can beadministered to a patient where the substance is converted in vivo bythe action of biochemicals within the patient's body, such as enzymes,to the active pharmaceutical ingredient. Examples of prodrugs includeesters of carboxylic acid groups, which can be hydrolyzed by endogenousesterases as are found in the bloodstream of humans and other mammals.

Any compound which can be converted in vivo to the active drug bychemical or biochemical transformations functions as a prodrug. Prodrugsof claimed compounds are covered under this invention.

Some examples of prodrugs within the scope of this invention include:

i. If the compound contains a hydroxyl group, the hydroxyl group may bemodified to form an ester, carbonate, or carbamate. Examples includeacetate, pivalate, methyl and ethyl carbonates, and dimethylcarbamate.The ester may also be derived from amino acids such as glycine, serine,or lysine.

ii. If the compound contains an amine group, the amine group may bemodified to form an amide. Examples include acetamide or derivatizationwith amino acids such as glycine, serine, or lysine.

Certain compounds of the invention and their salts may exist in morethan one crystal form and the present invention includes each crystalform and mixtures thereof. In addition, the compounds of the presentinvention can exist in unsolvated as well as solvated forms withpharmaceutically acceptable solvents such as water to form hydrates oradducts with alcohols such as C₁₋₄-alkanols, and the like. Furthermore,compounds of this invention can be isolated in association with solventmolecules by crystallization from evaporation of an appropriate solvent.Such solvents include but are not limited to toluene, tetrahydrofuran,dioxane, dimethylformamide, acetonitrile, acetates such as methylacetate, ethyl acetate, butyl acetate, isobutyl acetate, propyl- andisopropyl acetate, ethers such as diethyl ether and ethyl ether,alcohols such as methanol, ethanol, 1- or 2-butanol, 1- or 2-propanol,pentanol, and dimethylsulfoxide. In general, a depiction for thecompound by structure or name is considered to embrace the compound inany form (e.g., by itself, as a hydrate, solvate, or otherwise in amixture).

In addition, where features or aspects of the invention are described interms of Markush groups, those skilled in the art will recognize thatthe invention is also thereby described in terms of any individualmember or subgroup of members of the Markush group. For example, if X isdescribed as selected from the group consisting of bromine, chlorine,and iodine, claims for X being bromine and claims for X being bromineand chlorine are fully described. Moreover, where features or aspects ofthe invention are described in terms of Markush groups, those skilled inthe art will recognize that the invention is also thereby described interms of any combination of individual members or subgroups of membersof Markush groups. Thus, for example, if X is described as selected fromthe group consisting of bromine, chlorine, and iodine, and Y isdescribed as selected from the group consisting of methyl, ethyl, andpropyl, claims for X being bromine and Y being methyl are fullydescribed.

Compositions and Combination Treatments

The S1P₁ compounds, their pharmaceutically acceptable salts orhydrolyzable esters of the present invention may be combined with apharmaceutically acceptable carrier to provide pharmaceuticalcompositions useful for treating the biological conditions or disordersnoted herein in mammalian species, and more preferably, in humans. Theparticular carrier employed in these pharmaceutical compositions mayvary depending upon the type of administration desired (e.g.intravenous, oral, topical, suppository, or parenteral).

In preparing the compositions in oral liquid dosage forms (e.g.suspensions, elixirs and solutions), typical pharmaceutical media, suchas water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents and the like can be employed. Similarly, when preparingoral solid dosage forms (e.g. powders, tablets and capsules), carrierssuch as starches, sugars, diluents, granulating agents, lubricants,binders, disintegrating agents and the like can be employed.

Another aspect of an embodiment of the invention provides compositionsof the compounds of the invention, alone or in combination with anotherS1P₁ inhibitor or another type of therapeutic agent, or both. As setforth herein, compounds of the invention include stereoisomers,tautomers, solvates, hydrates, salts including pharmaceuticallyacceptable salts, and mixtures thereof. Compositions containing acompound of the invention can be prepared by conventional techniques,e.g. as described in Remington: The Science and Practice of Pharmacy,19th Ed., 1995, incorporated by reference herein. The compositions canappear in conventional forms, for example capsules, tablets, aerosols,solutions, suspensions or topical applications.

Typical compositions include a compound of the invention and apharmaceutically acceptable excipient which can be a carrier or adiluent. For example, the active compound will usually be mixed with acarrier, or diluted by a carrier, or enclosed within a carrier which canbe in the form of an ampoule, capsule, sachet, paper, or othercontainer. When the active compound is mixed with a carrier, or when thecarrier serves as a diluent, it can be solid, semi-solid, or liquidmaterial that acts as a vehicle, excipient, or medium for the activecompound. The active compound can be adsorbed on a granular solidcarrier, for example contained in a sachet. Some examples of suitablecarriers are water, salt solutions, alcohols, polyethylene glycols,polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin,lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar,cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin,acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid,fatty acids, fatty acid amines, fatty acid monoglycerides anddiglycerides, pentaerythritol fatty acid esters, polyoxyethylene,hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrieror diluent can include any sustained release material known in the art,such as glyceryl monostearate or glyceryl distearate, alone or mixedwith a wax.

The formulations can be mixed with auxiliary agents which do notdeleteriously react with the active compounds. Such additives caninclude wetting agents, emulsifying and suspending agents, salt forinfluencing osmotic pressure, buffers and/or coloring substancespreserving agents, sweetening agents or flavoring agents. Thecompositions can also be sterilized if desired.

The route of administration can be any route which effectivelytransports the active compound of the invention which inhibits theenzymatic activity of the focal adhesion kinase to the appropriate ordesired site of action, such as oral, nasal, pulmonary, buccal,subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot,subcutaneous, intravenous, intraurethral, intramuscular, intranasal,ophthalmic solution or an ointment, the oral route being preferred.

For parenteral administration, the carrier will typically comprisesterile water, although other ingredients that aid solubility or serveas preservatives can also be included. Furthermore, injectablesuspensions can also be prepared, in which case appropriate liquidcarriers, suspending agents and the like can be employed.

For topical administration, the compounds of the present invention canbe formulated using bland, moisturizing bases such as ointments orcreams.

If a solid carrier is used for oral administration, the preparation canbe tabletted, placed in a hard gelatin capsule in powder or pellet formor it can be in the form of a troche or lozenge. If a liquid carrier isused, the preparation can be in the form of a syrup, emulsion, softgelatin capsule or sterile injectable liquid such as an aqueous ornon-aqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oilsuspensions which can be prepared using a suitable dispersant or wettingagent and a suspending agent Injectable forms can be in solution phaseor in the form of a suspension, which is prepared with a solvent ordiluent. Acceptable solvents or vehicles include sterilized water,Ringer's solution, or an isotonic aqueous saline solution.Alternatively, sterile oils can be employed as solvents or suspendingagents. Preferably, the oil or fatty acid is non-volatile, includingnatural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation can also be a powder suitable forreconstitution with an appropriate solution as described above. Examplesof these include, but are not limited to, freeze dried, rotary dried orspray dried powders, amorphous powders, granules, precipitates, orparticulates. For injection, the formulations can optionally containstabilizers, pH modifiers, surfactants, bioavailability modifiers andcombinations of these. The compounds can be formulated for parenteraladministration by injection such as by bolus injection or continuousinfusion. A unit dosage form for injection can be in ampoules or inmulti-dose containers.

The formulations of the invention can be designed to provide quick,sustained, or delayed release of the active ingredient afteradministration to the patient by employing procedures well known in theart. Thus, the formulations can also be formulated for controlledrelease or for slow release.

Compositions contemplated by the present invention can include, forexample, micelles or liposomes, or some other encapsulated form, or canbe administered in an extended release form to provide a prolongedstorage and/or delivery effect. Therefore, the formulations can becompressed into pellets or cylinders and implanted intramuscularly orsubcutaneously as depot injections. Such implants can employ known inertmaterials such as silicones and biodegradable polymers, e.g.,polylactide-polyglycolide. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides).

For nasal administration, the preparation can contain a compound of theinvention which inhibits the enzymatic activity of the focal adhesionkinase, dissolved or suspended in a liquid carrier, preferably anaqueous carrier, for aerosol application. The carrier can containadditives such as solubilizing agents, e.g., propylene glycol,surfactants, absorption enhancers such as lecithin (phosphatidylcholine)or cyclodextrin, or preservatives such as parabens.

For parenteral application, particularly suitable are injectablesolutions or suspensions, preferably aqueous solutions with the activecompound dissolved in polyhydroxylated castor oil.

Dosage forms can be administered daily, or more than once a day, such astwice or thrice daily. Alternatively dosage forms can be administeredless frequently than daily, such as every other day, or weekly, if foundto be advisable by a prescribing physician.

An embodiment of the invention also encompasses prodrugs of a compoundof the invention which on administration undergo chemical conversion bymetabolic or other physiological processes before becoming activepharmacological substances. Conversion by metabolic or otherphysiological processes includes without limitation enzymatic (e.g.,specific enzymatically catalyzed) and non-enzymatic (e.g., general orspecific acid or base induced) chemical transformation of the prodruginto the active pharmacological substance. In general, such prodrugswill be functional derivatives of a compound of the invention which arereadily convertible in vivo into a compound of the invention.Conventional procedures for the selection and preparation of suitableprodrug derivatives are described, for example, in Design of Prodrugs,ed. H. Bundgaard, Elsevier, 1985.

In another embodiment, there are provided methods of making acomposition of a compound described herein including formulating acompound of the invention with a pharmaceutically acceptable carrier ordiluent. In some embodiments, the pharmaceutically acceptable carrier ordiluent is suitable for oral administration. In some such embodiments,the methods can further include the step of formulating the compositioninto a tablet or capsule. In other embodiments, the pharmaceuticallyacceptable carrier or diluent is suitable for parenteral administration.In some such embodiments, the methods further include the step oflyophilizing the composition to form a lyophilized preparation.

The compounds of the invention can be used therapeutically incombination with i) one or more other S1P₁ inhibitors and/or ii) one ormore other types of protein kinase inhibitors and/or one or more othertypes of therapeutic agents which can be administered orally in the samedosage form, in a separate oral dosage form (e.g., sequentially ornon-sequentially) or by injection together or separately (e.g.,sequentially or non-sequentially).

Accordingly, in another embodiment the invention provides combinations,comprising:

-   -   a) a compound of the invention as described herein; and    -   b) one or more compounds comprising:        -   i) other compounds of the present invention,        -   ii) other medicaments adapted for treatment of a            malcondition for which activation of S1P₁ is medically            indicated, for example multiple sclerosis, transplant            rejection, or adult respiratory distress syndrome.

Combinations of the invention include mixtures of compounds from (a) and(b) in a single formulation and compounds from (a) and (b) as separateformulations. Some combinations of the invention can be packaged asseparate formulations in a kit. In some embodiments, two or morecompounds from (b) are formulated together while a compound of theinvention is formulated separately.

The dosages and formulations for the other agents to be employed, whereapplicable, will be as set out in the latest edition of the Physicians'Desk Reference, incorporated herein by reference.

Methods of Treatment

In certain embodiments, the present invention encompasses orallybioavailable compounds that specifically agonize S1P₁ without binding(S1P₂, S1P₃ and S1P₄), or having significant specificity over (S1P₅),other EDG receptors. A selective S1P₁ agonist can be used to treatdiseases with an autoimmune, hyperactive immune-response, angiogenesisor inflammatory components, but would not be limited to such conditions.Selective S1P₁ agonists have advantages over current therapies byincreasing the therapeutic window because of reduced toxicity due toengagement of other EDG receptors.

In certain embodiments, the present invention encompasses compounds thatbind with high affinity and specificity to the S1P₁ receptor in anagonist manner. Upon ligation of the S1P₁ receptor with agonist,signaling proceeds through G_(αi), inhibiting the generation of cAMP byadenylate cyclase.

In certain embodiments, the present invention provides a method foractivating or agonizing (i.e., to have an agonic effect, to act as anagonist) a sphingosine-1-phosphate receptor subtype, such as S1P₁, witha compound of the invention. The method involves contacting the receptorwith a suitable concentration of an inventive compound to bring aboutactivation of the receptor. The contacting can take place in vitro, forexample in carrying out an assay to determine the S1P receptoractivation activity of an inventive compound undergoing experimentationrelated to a submission for regulatory approval.

In certain embodiments, the method for activating an S1P receptor, suchas S1P₁, can also be carried out in vivo, that is, within the livingbody of a mammal, such as a human patient or a test animal. Theinventive compound can be supplied to the living organism via one of theroutes as described above, e.g., orally, or can be provided locallywithin the body tissues, for example by injection of a tumor within theorganism. In the presence of the inventive compound, activation of thereceptor takes place, and the effect thereof can be studied.

An embodiment of the present invention provides a method of treatment ofa malcondition in a patient for which activation of an SIP receptor,such as S1P₁, is medically indicated, wherein the patient isadministered the inventive compound in a dosage, at a frequency, and fora duration to produce a beneficial effect on the patient. The inventivecompound can be administered by any suitable means, examples of whichare described above.

Preparation of Certain Embodiments

Reagents: (i) KH₂PO₄, H₂O₂, NaClO₂, CH₃CN; (ii) H₂NNHCSNH₂, POCl₃; (iii)CuBr₂, isoamylnitrite, CH₃CN.

Reagents: (i) R¹-boronic acid, K₂CO₃, Pd(PPh₃)₄, DME, H₂O; (ii) NBS,DMF.

Reagents: (i) R¹—I, Pd(PPh₃)₂Cl₂, THF; (ii) Br₂, AcOK, AcOH.

Reagents: (i) R¹—Br, K₂CO₃, Pd(PPh₃)₄, DME, H₂O; (ii) NBS, DMF.

Reagents: (i) (S)-2-methyl-CBS-oxazaborolidine, BH₃-Me₂S, toluene, DCM;(ii) PG-Cl, (where PG is protecting group), e.g. TBSCl, imidazole, DMF;(iii) bis(pinacolato)diboron, PdCl₂(dppf).CH₂Cl₂, KOAc, 1,4-dioxane.

The (S)-enantiomer was prepared in same manner as outlined in Scheme 5by the use of (R)-2-methyl-CBS-oxazaborolidine in Step i. The racemicmaterial can be prepared in an analogous manner using NaBH₄ as reducingagent in Step i.

Reagents: (i) (R)-2-methylpropane-2-sulfinamide, NaBH₄, THF, toluene;(ii) 4N HCl, 1,4-dioxane; (iii) PG=di-tert-butyldicarbonate,triethylamine, DCM; (iv) bis(pinacolato)diboron, PdCl₂(dppf).CH₂Cl₂,KOAc, 1,4-dioxane.

The (S)-enantiomer was prepared in same manner as outlined in Scheme 6by the use of (S)-2-methylpropane-2-sulfinamide in Step i.

Reagents: (i) K₂CO₃, Pd(PPh₃)₄, DME, H₂O; (ii) NaOiPr, iPrOH; (iii)deprotection, e.g. TBAF, THF or HCl, 1,4-dioxane.

The (S)-enantiomers were prepared in same manner as outlined in Scheme 7by the use of(S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silanein Step i. Racemic indanol was prepared in same manner using racemictert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silanein Step i.

Reagents: (i) K₂CO₃, Pd(PPh₃)₄, DME, H₂O; (ii) NaOiPr, iPrOH; (iii) 4NHCl, 1,4-dioxane; (iv) (a) R′-LG or R″-LG, where LG represents a leavinggroup, K₂CO₃, CH₃CN; (b) R³—CO₂H or R⁴—CO₂H, HOBt, EDC, DMF or R³—COClor R⁴—CO₂H, TEA, DCM; (c) R³—SO₂Cl or R⁵—SO₂Cl, TEA, DCM (d) R⁴—CHO,HOAc, NaBH₄ or NaCNBH₃ or Na(OAc)₃BH, MeOH; (e) R³—OCOCl or R⁴—OCOCl,DIEA, DMF; (f) HN(R⁷R⁷), CDI, TEA, DCM; (g) H₂NSO₂NH₂, D, dioxane; (h)dimethyloxirane, D, EtOH; (x) (a) If R′ or R″═H, then reactions(ix)(a-d) can be performed; (b) If R′ or R″ contains an ester then (i)hydrolysis NaOH, EtOH or (ii) reduction NaBH₄, MeOH can be performed;(c) If R′ or R″ contains an acid then couplings HN(R⁷R⁷), HOBt, EDC, DMFcan be performed; (d) If R′ or R″ contains an appropriate activatedalkene then Michael additions HN(R⁷R⁷), DMF can be performed.

The (S)-enantiomers were prepared in same manner as outlined in Scheme 8by the use of (S)-tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamatein Step i.

Reagents: (i) (3-cyano-4-isopropoxyphenyl)boronic acid, K₂CO₃,Pd(PPh₃)₄, DME, H₂O; (ii) (R)-, (S)-, or racemictert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane,K₂CO₃, Pd(PPh₃)₄, DME, H₂O; (iii) TBAF, THF.

Reagents: (i) (ii) (R)-, (S)-, or racemictert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane,K₂CO₃, Pd(PPh₃)₄, DME, H₂O; (ii) (3-cyano-4-isopropoxyphenyl)boronicacid, K₂CO₃, Pd(PPh₃)₄, DME, H₂O; (iii) TBAF, THF.

EXAMPLES General Methods

¹H NMR (400 MHz) and ¹³C NMR (100 MHz) were obtained in solution ofdeuteriochloroform (CDCl₃), deuteriomethanol (CD₃OD) or dimethylsulfoxide-D₆ (DMSO). NMR spectra were processed using Mestrec 5.3.0 and6.0.1. ¹³C NMR peaks that are bracketed are two rotomers of the samecarbon. Mass spectra (LCMS) were obtained using an Agilent 1100/6110HPLC system equipped with a Thompson ODS-A, 100 A, 5μ (50×4.6 mm) columnusing water with 0.1% formic acid as the mobile phase A, andacetonitrile with 0.1% formic acid as the mobile phase B. The gradientwas 20-100% with mobile phase B over 2.5 min then held at 100% for 2.5mins. The flow rate was 1 mL/min. Unless otherwise indicated, the LCMSdata provided uses this method. For more hydrophobic compounds, thefollowing gradient was used, denoted as Method 1: 40-95% over 0.5 min,hold at 95% for 8.5 min, then return to 40% over 2 min, with a flow rateof 1 mL/min. Final compounds were checked for purity using Method 2: 5%for 1 min, 5-95% over 9 min, then hold at 95% for 5 min, with a flowrate of 1 mL/min. Method 3: 20-100% over 2.5 min then held at 100% for4.5 min, with the flow rate of 1 mL/min. Enantiomeric excess wasdetermined by integration of peaks that were separated on a ChiralpakAD-H, 250×4.6 mm column at a flow rate of 1 mL/min and an isocraticmobile phase. Unless otherwise indicated, the chiral data provided usesthis method. Alternatively, chiral separations were performed under thefollowing conditions, denoted as Chiral Method 1: Chiralpak AY-H,250×4.6 mm column at a flow rate of 1 mL/min and an isocratic mobilephase. Chiral Method 2: Chiralcel OZ-3, 150×4.6 mm at flow rate of 1mL/min and an isocratic mobile phase. The pyridine, dichloromethane(DCM), tetrahydrofuran (THF), and toluene used in the procedures werefrom Aldrich Sure-Seal bottles kept under nitrogen (N₂). All reactionswere stirred magnetically and temperatures are external reactiontemperatures. Chromatographies were carried out using a Combiflash Rfflash purification system (Teledyne Isco) equipped with Redisep(Teledyne Isco) silica gel (SiO₂) columns. Preparative HPLCpurifications were done on Varian ProStar/PrepStar system using watercontaining 0.05% trifluoroacetic acid as mobile phase A, andacetonitrile with 0.05% trifluoroacetic acid as mobile phase B. Thegradient was 10-80% with mobile phase B over 12 min, hold at 80% for 2min, and then return to 10% over 2 min with flow rate of 22 mL/min.Other methods similar to this may have been employed. Fractions werecollected using a Varian Prostar fraction collector and were evaporatedusing a Savant SpeedVac Plus vacuum pump. Compounds with salt-ablecenters were presumed to be the trifluoroacetic acid (TFA) salt.Microwave heating was performed using a Biotage Initiator microwavereactor equipped with Biotage microwave vessels. The followingabbreviations are used: ethyl acetate (EA), triethylamine (TEA), diethylamine (DEA), hydroxybenzotriazole (HOBt),1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC),isopropanol (IPA), dimethylformamide (DMF), dimethyl acetamide (DMA).Norit is activated charcoal.

Experimental Procedures 3-cyano-4-fluorobenzoic acid

To a solution of 3-cyano-4-fluorobenzaldehyde (45 g, 301 mmol) in CH₃CN(450 mL) was added potassium phosphate monobasic (24 g, 176 mmol) inwater (225 mL) and 30% hydrogen peroxide in water (30 mL). The reactionmixture was cooled to 0° C. and sodium chlorite (60 g, 663 mmol) inwater (450 mL) was added dropwise over 2 h. The resulting yellowsuspension was stirred at room temperature until production of oxygenceased (4 h). Sodium sulfite (30 g, 238 mmol) in water (100 mL) wasadded and the reaction mixture stirred for 1 h. The reaction wasquenched with 2N HCl (500 mL) and the resulting solid was filtered andwashed with water. The aqueous phase was extracted with EA (2×500 mL).The combined organic layers were washed with brine (200 mL), dried overMgSO₄, concentrated, and combined with the collected solid to produce atotal of 48.5 g (97%) of crude 3-cyano-4-fluorobenzoic acid as a whitesolid. LCMS-ESI (m/z) calculated for C₈H₄FNO₂: 165.0. found 166.1[M+H]⁺, t_(R)=2.54 min. ¹H NMR (400 MHz, DMSO) δ 13.60 (s, 1H), 8.41(dd, J=6.3, 2.1 Hz, 1H), 8.30 (ddd, J=8.8, 5.3, 2.2 Hz, 1H), 7.66 (t,J=9.0 Hz, 1H).

5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile (TDZ INT-I)

To a stirred mixture of 3-cyano-4-fluorobenzoic acid (37.3 g, 225 mmol)and thiosemicarbazide (22.6 g, 248 mmol) was added POCl₃ (148 mL) at 0°C. The reaction mixture was stirred at 0° C. for 1 h and then heated to85° C. for 6 h. The resulting yellow solution was cooled to roomtemperature and concentrated to 50% volume. The residue was cooled to 0°C. and water was added (300 mL) drop wise. (Caution: exothermic andviolent reaction with gas evolution). The mixture was heated to 90° C.for 1 h then cooled to room temperature. EA was added EA (300 mL) andthe reaction mixture stirred for 10 min and before filtration. Thecollected solid was dispersed into water (270 mL), cooled to 0° C., andneutralized with 50% NaOH aqueous solution to pH8. The resulting solidwas filtered, washed thoroughly with water, and dried under high vacuumto afford 26 g (52%) of5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-1 as paleyellow solid which was used in next experiment without purification.LCMS-ESI (m/z) calculated for C₉H₅FN₄S: 220.0. found 221.1 [M+H]⁺,t_(R)=2.44 min. ¹H NMR (400 MHz, DMSO) δ 8.29 (dd, J=6.1, 2.3 Hz, 1H),8.19 (ddd, J=8.9, 5.2, 2.4 Hz, 1H), 7.64 (t, J=9.0 Hz, 1H), 7.58 (s,2H). ¹³C NMR (101 MHz, DMSO) δ 169.82, 164.25, 161.68, 133.68, 131.65,128.96, 117.96, 113.77, 101.59.

5-(3,4-Diethoxyphenyl)-1,3,4-thiadiazol-2-amine TDZ INT-2 wassynthesized in a similar manner as5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-1 using3,4-diethoxybenzoic acid. LCMS-ESI (m/z) calculated for C₁₂H₁₅N₃O₂S:265.3. found 266.1. [M+H]⁺, t_(R)=2.58 min. ¹H NMR (400 MHz, DMSO) δ7.45-7.31 (m, 1H), 7.23 (dd, J=8.3, 2.1 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H),4.31-3.94 (m, 4H), 3.4 (s, 2H), 1.42 (qd, J=6.8, 3.3 Hz, 6H).

5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile (TDZ INT-3)

To a stirred solution of5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-1 (25 g,113 mmol) and copper bromide (30.4 g, 136 mmol) in CH₃CN (400 mL) wasadded isoamylnitrite (15.9 g, 136 mmol) and the mixture stirred at roomtemperature for 5 h. The reaction was partitioned between EA (2×250 mL)and 1N HCl (250 mL). The combined organic extracts were washed withbrine, dried over MgSO₄, and concentrated. The crude product wascrystallized from EA to afford 23.5 g (73%) of5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3 as apale yellow solid. LCMS-ESI (m/z) calculated for: C₉H₃BrFN₃S: 284.1.found 285.9 [M+H]⁺, t_(R)=3.27 min. ¹H NMR (400 MHz, DMSO) δ 8.58 (dd,J=6.0, 2.3 Hz, 1H), 8.40 (ddd, J=8.9, 5.1, 2.4 Hz, 1H), 7.76 (t, J=9.0Hz, 1H); ¹³C NMR (101 MHz, DMSO) δ 168.61, 162.47, 140.32, 134.88,133.38, 126.13, 117.88, 112.91.

2-Bromo-5-(3,4-diethoxyphenyl)-1,3,4-thiadiazole TDZ INT-4 wassynthesized in similar manner as described for the synthesis of2-bromo-5-(3,4-diethoxyphenyl)-1,3,4-thiadiazole TDZ INT-3 using5-(3,4-diethoxyphenyl)-1,3,4-thiadiazol-2-amine. LCMS-ESI (m/z)calculated for: C₁₂H₁₃BrN₂O₂S: 328.0. found 329.1 [M+H]⁺, t_(R)=2.58min. ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J=2.1 Hz, 1H), 7.25 (d, J=2.1Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.10 (dq, J=8.9, 7.0 Hz, 4H), 1.42 (t,J=7.0 Hz, 6H).

2-fluoro-5-(thiazol-2-yl)benzonitrile (THZ INT-1)

A solution of 2-bromothiazole (25 g, 153.4 mmol),(3-cyano-4-fluorophenyl)boronic acid (25.3 g, 153.3 mmol), K₂CO₃ (63.6g, 460 mmol) and 3:1 DME/H₂O (205 mL) was purged with N₂ for 1 h beforethe addition of Pd(PPh₃)₄ (9.2 g, 7.9 mmol). The mixture was furtherdegassed with N₂ for 5 min and then heated to 85° C. for 7 h under N₂.Upon cooling, the reaction mixture was diluted with EA (250 mL), washedwith water (200 mL) and brine (200 mL), and dried over MgSO₄. Thereaction mixture was filtered and concentrated to give beige solid. Thecrude product was purified by recrystallization from 20% EA/hexanes toafford 22 g (71%) of 2-fluoro-5-(thiazol-2-yl)benzonitrile THZ INT-1 asa pale yellow solid. LCMS-ESI (m/z) calculated for C₁₀H₅FN₂S: 204.2.found 205.0 [M+H]⁺, t_(R)=3.26 min. ¹H NMR (400 MHz, CDCl₃) δ 8.21-8.16(m, 1H), 8.15-8.08 (m, 1H), 7.86-7.81 (m, 1H), 7.36-7.32 (m, 1H),7.27-7.21 (m, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 164.31, 162.22, 143.73,132.68, 131.28, 128.34, 119.94, 116.98, 113.10.

5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile (THZ INT-2)

To 2-fluoro-5-(thiazol-2-yl)benzonitrile (21.8 g, 106.7 mmol) inanhydrous DMF (200 mL) was added recrystallized N-bromosuccinimide (22.7g, 128 mmol). The reaction mixture was stirred at room temperature for23 h under N₂. The reaction mixture was basified with 1N NaOH and washedwith EA and brine. The combined organic layers were dried over MgSO₄,filtered, and concentrated to yield orange oil. The crude product waspurified by silica gel flash chromatography (20% EA/Hexanes) to produce21 mg (70%) of 5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 ashalf-white solid. LCMS-ESI (m/z) calculated for C₁₀H₄BrFN₂S: 283.1.found 284.9 [M+H]⁺, t_(R)=3.82 min. ¹H NMR (400 MHz, CDCl₃) δ 8.15 (dd,J=5.9, 2.3 Hz, 1H), 8.08 (ddd, J=8.8, 4.9, 2.3 Hz, 1H), 7.78 (d, J=4.8Hz, 1H), 7.31 (t, J=8.6 Hz, 1H).

(S)-4-bromo-2,3-dihydro-1H-inden-1-ol (IND INT-1)

To a 100 mL 3-neck flask equipped with an internal thermometer and anaddition funnel was added (R)-(+)-2-methyl-CBS-oxazaborolidine (1.6 mL,1M solution in toluene) and borane-dimethylsulfide (150 uL) under N₂.The reaction was stirred at room temperature for 10 min then dilutedwith DCM (10 mL). Borane-dimethylsulfide (6.0 mL) was added and thereaction cooled to −20° C. A solution of4-Bromo-2,3-dihydro-1H-inden-1-one (2.5 g, 11.8 mmol) in DCM (10 mL) wasadded dropwise over 20 min while maintaining the reaction temperature at−20±5° C. The reaction was stirred for 2 h after the addition wascomplete, then quenched by the dropwise addition of MeOH (10 mL). Thereaction mixture was diluted with MeOH (20 mL) and the solvent distilledat atmospheric pressure. MeOH (30 mL) was added in two portions and thedistillation was repeated twice. All the solvent was evaporated to givea solid which was purified by silica gel column chromatography(EA/hexanes) and recrystallization from 5:1 hexane/EA (30 mL) to provide1.56 g (62%) of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol as a white powderIND INT-1. LCMS-ESI (m/z) calculated for C₉H₉BrO: 213.1. found 196.9[M-OH]⁺, t_(R)=3.06 min. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (d, J=7.9 Hz,1H), 7.33 (d, J=7.5 Hz, 1H), 7.10 (t, J=7.7 Hz, 1H), 5.29 (dd, J=12.6,6.9 Hz, 1H), 3.05 (ddd, J=16.6, 8.7, 4.6 Hz, 1H), 2.87-2.71 (m, 1H),2.50 (dddd, J=13.2, 8.4, 7.0, 4.6 Hz, 1H), 1.94 (dddd, J=13.5, 8.8, 6.6,5.5 Hz, 1H), 1.80 (d, J=7.1 Hz, 1H). ¹³C NMR (101 MHz, CDCl₃) δ 146.82,143.50, 131.24, 128.58, 123.21, 120.25, 76.83, 34.69, 31.19. ChiralHPLC: (S)-4-bromo-2,3-dihydro-1H-inden-1-ol was eluted using 10% IPA inhexanes: >99.9% % ee, t_(R)=6.27 min.

(R)-4-bromo-2,3-dihydro-1H-inden-1-ol IND INT-2 was prepared in ananalogous manner using (S)-(−)-2-methyl-CBS-oxazaborolidine: 97.6% ee,t_(R) for (R)-enantiomer=5.83 min.

(S)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane(IND INT-3)

To a solution of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol IND INT-1 (1.56g, 7.3 mm) in DMF (5 mL) was added TBDMSCl (1.3 g, 8.7 mmol) andimidazole (1.24 g, 18.3 mmol) and the reaction mixture was stirred atroom temperature overnight. The reaction mixture was diluted withsaturated NaHCO₃ solution (30 mL) and extracted with EA (2×50 mL). Theorganic layers were washed with water and brine, and dried over MgSO₄.The crude product was purified by chromatography (EA/hexane) to afford2.1 g (88%) of(S)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilaneIND INT-3 as white solid. LCMS-ESI (m/z) calculated for C₁₅H₂₃BrOSi:327.3; no M⁺ observed, t_(R)=5.73 min (Method 2). ¹H NMR (400 MHz,CDCl₃) δ 7.35 (d, J=7.8 Hz, 1H), 7.22 (d, J=7.4 Hz, 1H), 7.07 (t, J=7.7Hz, 1H), 5.28 (t, J=7.1 Hz, 1H), 3.00 (ddd, J=16.4, 9.1, 2.9 Hz, 1H),2.73 (dt, J=16.5, 8.3 Hz, 1H), 2.42 (dddd, J=12.8, 8.0, 7.1, 3.0 Hz,1H), 1.91 (dtd, J=12.8, 8.9, 7.1 Hz, 1H), 0.98-0.88 (m, 9H), 0.14 (d,J=7.4 Hz, 6H).

(R)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilaneIND INT-4 was prepared in an analogous fashion using(R)-4-bromo-2,3-dihydro-1H-inden-1-ol.

(±)-4-bromo-2,3-dihydro-1H-inden-1-ol (IND INT-5)

To a stirring solution of 4-bromoindanone (3 g, 14.2 mmol) in anhydrousEtOH (30 mL) was added sodium borohydride (0.36 g, 9.5 mmol) and silicagel (2 g) at 0° C. The reaction was stirred at 0° C. for 20 min and wasallowed to stir at room temperature for 2 h. The reaction mixture wasquenched with saturated NaHCO₃ solution (10 mL) and concentrated toremove EtOH. The aqueous layer was extracted with EA (3×20 mL) and theorganic phase was dried over MgSO₄. After concentration, the crudeproduct was purified by chromatography (EA/hexane) to yield(±)-4-bromo-2,3-dihydro-1H-inden-1-ol IND INT-5 (2.56 g, 85%) as a whitesolid. LCMS-ESI (m/z) calculated for C₉H₉BrO: 213.07. found 195.0[M−H₂O]¹, t_(R)=3.07 min. ¹H NMR (400 MHz, CDCl₃) δ 7.35 (d, J=7.9, 1H),7.27 (d, J=7.4, 1H), 7.05 (t, J=7.7, 1H), 5.23 (t, J=6.2, 1H), 3.00(ddd, J=16.6, 8.8, 4.6, 1H), 2.84-2.66 (m, 1H), 2.45 (dddd, J=13.2, 8.4,7.0, 4.6, 1H), 1.96-1.70 (m, 2H).

(S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane(IND INT-6)

A solution of(S)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilaneIND INT-3 (0.2 mg, 0.61 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (0.17 g,0.67 mmol), and potassium acetate (1.8 g, 0.45 mmol) in anhydrous1,4-dioxane (4 mL) was degassed by passing N₂ through the solution for10 min. PdCl₂(dppf).CH₂Cl₂ (99 mg, 0.12 mmol) was added and the reactionmixture heated at 85° C. overnight. The solvent was removed undervacuum. The residue was dissolved in EA (10 mL), and filtered throughcelite. The filtrate was washed with water and brine, dried over MgSO₄and filtered. The crude product was purified by chromatography(EA/hexanes) to afford 26 mg (45%)(S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silaneIND INT-6 as a white solid. LCMS-ESI (m/z) calculated for C₂₁H₃₅BO₃Si:374.4. found 245.0 [M-OTBS]⁺, t_(R)=6.57 min (Method 1). ¹H NMR (400MHz, CDCl₃) δ 7.66 (d, J=7.2 Hz, 1H), 7.36 (dd, J=8.7, 4.3 Hz, 1H), 7.19(dd, J=9.4, 5.4 Hz, 1H), 5.21 (t, J=7.0 Hz, 1H), 3.26 (ddd, J=16.9, 8.9,3.0 Hz, 1H), 2.86 (dt, J=16.8, 8.3 Hz, 1H), 2.48-2.23 (m, 1H), 1.86(dtd, J=12.6, 8.8, 7.0 Hz, 1H), 1.38-1.23 (m, 12H), 1.00-0.81 (m, 9H),0.22-0.07 (m, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 149.59, 145.08, 134.83,134.75, 126.92, 125.78, 83.39, 76.52, 36.29, 30.78, 25.96, 24.96, 18.28,−4.29, −4.55.

(R)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silaneIND INT-7 was prepared in an analogous fashion using(R)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilaneIND INT-4. Racemic(±)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silaneIND INT-8 was prepared in an analogous fashion from IND INT-5.

General Procedure 1: Coupling of Heterocyclic Bromide to IndanolBoronate

A 20 mL microwave vial was charged sequentially with heterocyclicbromide (1 eq), (R)—(S)- or racemic indanol dioxaborolane (IND INT-6, 7or 8, 1 eq), DME:H₂O (3:1, 0.05 M) and potassium carbonate (3 eq). Themixture was degassed by bubbling N₂ gas through the stirring solutionfor 10 min. Pd(PPh₃)₄ (0.07 eq) was added and the mixture degassed foradditional 2 min. The vial as was capped and subjected to microwaveirradiation at 100° C. until reaction completed (40-60 min). Additionalbromide was added if needed. The vial was cooled to room temperature,diluted with EA (10× volume), washed with water and brine, dried overMgSO₄, and concentrated. The crude product was purified by silica gelcolumn chromatography (EA/hexanes).

(S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile

Prepared using General Procedure 1: A 20 mL microwave vial was chargedwith 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3(30 mg, 0.1 mmol),(S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silaneIND INT-6 (43.6 mg, 0.11 mmol), potassium carbonate (44 mg, 0.32 mmol)and a 3:1 mixture of DME/H₂O (2 mL). The reaction mixture was degassedby bubbling N₂ gas through the stirring solution for 10 min. Pd(PPh₃)₄was added and mixture degassed for additional 2 min. The vial wassubjected to microwave irradiation at 100° C. for 40 min. The reactionmixture was cooled to room temperature, diluted with EA (10 mL), andwashed with water and brine. The organic layer dried over MgSO₄,concentrated, and purified by silica gel chromatography (EA/hexanes) toprovide 25 mg (44%) of(S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrileas a light yellow solid. LCMS-ESI (m/z) calculated for C₂₄H₂₆FN₃OSSi:451.15. found 452.1 [M+H]⁺, t_(R)=4.53 min (Method 1). ¹H NMR (400 MHz,CDCl₃) δ 8.34-8.25 (m, 2H), 7.85 (d, J=7.6 Hz, 1H), 7.49 (d, J=7.5 Hz,1H), 7.44-7.34 (m, 2H), 5.34 (t, J=7.1 Hz, 1H), 3.46 (ddd, J=16.8, 9.0,2.8 Hz, 1H), 3.13 (dt, J=16.8, 8.3 Hz, 1H), 2.61-2.50 (m, 1H), 2.08-1.96(m, 1H), 0.98-0.95 (m, 9H), 0.22-0.17 (m, 6H).

(R)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrilewas prepared in an analogous fashion using(R)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silaneIND INT-7.

(S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-fluorobenzonitrile

Prepared using General Procedure 1. A solution of5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 (0.12 g, 0.42mmol),(S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silaneIND INT-6 (0.16 g, 0.42 mmol), potassium carbonate (0.176 g, 1.2 mmol)and 3:1 mixture of DME/H₂O (2 mL) was degassed with N₂ for 10 min beforethe addition of Pd(PPh₃)₄ (0.034 g, 0.03 mmol). The mixture reaction wasdegassed with N₂ for additional 2 min and then heated under microwave at90° C. for 1.5 h. Upon cooling, the reaction mixture was diluted with EA(20 mL) and washed with brine (20 mL). The combined organic layers weredried over MgSO₄, filtered, and concentrated. The crude product waspurified by silica gel flash chromatography (30% EA/hexanes) to produce0.116 g (60%) of(S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-fluorobenzonitrileas a white solid. LCMS-ESI (m/z) calculated for C₂₅H₂₇FN₂OSSi: 450.6.found 451.1 [M+H]⁺, t_(R)=4.86 min (Method 1). ¹H NMR (400 MHz, CDCL₃) δ8.30-8.14 (m, 2H), 7.95 (s, 1H), 7.45 (dd, J=7.0, 0.9, 1H), 7.32 (ddd,J=23.9, 14.6, 11.0, 3H), 5.32 (t, J=7.0, 1H), 3.19 (ddd, J=15.9, 8.8,2.7, 1H), 2.95 (dt, J=16.1, 8.1, 1H), 2.59-2.40 (m, 1H), 2.08-1.89 (m,1H), 0.94 (s, 9H), 0.17 (dd, J=13.7, 7.8, 6H).

(R)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-fluorobenzonitrilewas prepared in an analogous fashion using(R)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane.

General Procedure 2: Displacement of Fluorine with Isopropoxide

To a stirred solution of the (R)- or (S)-fluorobenzene derivative (1 eq)in IPA (0.02 M) was added sodium isopropoxide (1.3 eq). The reaction wasstirred at 60° C. under N₂ for 2 h or until reaction is complete. Uponcooling the solvent was evaporated to dryness and the product waspurified by silica gel column chromatography (EA/hexanes).

(S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile

Prepared using General Procedure 2: To a solution of(S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile(21 mg, 0.04 mmol) in IPA (2 mL) was added sodium isopropoxide (5 mg,0.06 mmol). The reaction mixture was heated at 60° C. for 2 h. Uponcooling, the solvent was evaporated and the product was purified by asilica gel column chromatography (EA/hexanes) to afford(S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile(15 mg, 68%). LCMS-ESI (m/z) calculated for C₂₈H₃₄N₂O₂SSi: 491.7. found492.2 [M+H]⁺, t_(R)=5.17 min (Method 1).

(R)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilewas prepared in an analogous fashion using(R)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile.

(S)-5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile

Prepared using General Procedure 2. To a solution of(S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-fluorobenzonitrile(116 mg, 0.25 mmol) in IPA (2 mL) was added sodium isopropoxide (21.1mg, 0.25 mmol). The reaction mixture was heated at 60° C. for 2 h. Uponcooling, the solvent was evaporated and the product was purified by asilica gel column chromatography (EA/hexanes) to afford 151 mg (88%) of(S)-5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxy-benzonitrileLCMS-ESI (m/z) calculated for C₂₈H₃₄N₂O₂SSi: 490.7. found 491.1 [M+H]⁺,t_(R)=6.81 min (Method 1).

(R)-5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilewas prepared in an analogous fashion using(R)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-fluorobenzonitrile.

General Procedure 3: Deprotection of Silyl protected Indanols

To a stirred solution of the (R)- or (S)-silyl protected indanol (1 eq)in anhydrous THF (0.06 M) was added 1 M tetrabutyl ammonium fluoride (5eq) in THF and the mixture was stirred at room temperature under N₂.Upon completion, the reaction mixture was diluted with EA (10× volume),and washed thoroughly with NaHCO₃, water and brine, dried over MgSO₄,and concentrated. The crude product was purified by silica gel columnchromatography (EA/hexanes).

Compounds 1-3, and 69-70 were prepared using a sequence of GeneralProcedures 1-3.

(S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile(Compound 1)

To a stirred solution of(S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile(21 mg, 0.06 mmol) in anhydrous THF (1 mL) was added 1M tetrabutylammonium fluoride (0.3 mL, 0.3 mmol) and the reaction mixture stirred atroom temperature overnight. The reaction mixture was diluted with EA (10mL), washed with saturated NaHCO₃ and brine, and dried over MgSO₄. Theproduct was purified by chromatography (EA/hexanes) to afford 8 mg (81%)of(S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile1 as a white solid. LCMS-ESI (m/z) calculated for C₂₁H₁₉N₃O₂S: 377.1.found 378.1 [M+H]⁺, t_(R)=3.67 min. ¹H NMR (400 MHz, CDCl₃) δ 8.28-8.07(m, 2H), 7.86 (d, J=7.5 Hz, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.40 (t, J=7.6Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 5.41-5.18 (m, 1H), 4.74 (dd, J=12.2,6.0 Hz, 1H), 3.48 (ddd, J=17.1, 8.7, 4.6 Hz, 1H), 3.30-3.06 (m, 1H),2.72-2.40 (m, 1H), 2.04 (ddd, J=13.6, 8.7, 6.5 Hz, 1H), 1.64 (s, 2H),1.44 (d, J=6.1 Hz, 5H). ¹³C NMR (101 MHz, CDCl₃) δ 167.61, 166.22,162.23, 147.58, 142.93, 134.04, 133.83, 129.81, 128.30, 127.45, 127.09,123.37, 116.14, 114.45, 104.34, 77.23, 76.71, 73.09, 36.24, 31.69,22.32.

(R)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile2 was prepared in an analogous fashion using(R)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile.

(S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile(Compound 70)

Prepared using General Procedure 3. To a solution of crude(S)-5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile(0.11 g, 0.22 mmol) in anhydrous THF (3 mL) was added 1.0 M solution ofTBAF (1.0 mL) in THF. The reaction mixture was stirred at roomtemperature for 2 h. The solvent was concentrated under vacuum and thereside purified by a silica gel chromatography to afford 35 mg (41%) of(S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile70 as white solid. LCMS-ESI (m/z): calcd for: C₂₂H₂₀N₂O₂S: 376.4. found377.1 [M+H]⁺, t_(R)=3.66 min. ¹H NMR (400 MHz, CDCl₃) δ 8.14-7.89 (m,2H), 7.82-7.62 (m, 1H), 7.35 (dd, J=7.5, 2.6 Hz, 2H), 7.22 (dd, J=15.0,7.5 Hz, 1H), 7.02-6.77 (m, 1H), 5.36-5.08 (m, 1H), 4.65 (hept, J=6.0 Hz,1H), 3.10 (ddd, J=16.1, 8.5, 4.6 Hz, 1H), 2.93-2.80 (m, 1H), 2.68-2.54(m, 1H), 2.44 (dddd, J=11.7, 8.3, 7.0, 4.7 Hz, 1H), 2.01-1.77 (m, 1H),1.41-1.29 (m, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 164.98, 161.11, 146.82,141.23, 140.87, 137.98, 132.11, 131.99, 128.40, 128.03, 127.91, 126.67,124.62, 116.13, 113.98, 103.76, 76.43, 72.55, 35.89, 30.78, 22.01.Chiral HPLC:(S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilewas eluted using 15% IPA in hexanes: 100% ee; t_(R)=24.19 min.

(R)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 69 was prepared in an analogous fashion using(R)-5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxy-benzonitrile:97% ee, t_(R) for (R)-enantiomer=47.32 min.

(S,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide(IND INT-9)

An oven dried 2 L RB flask was charged with(S)-2-methylpropane-2-sulfinamide (31.5 g, 260 mmol), titaniumtetraethoxide (81 g, 355 mmol) and anhydrous toluene (250 mL). Thereaction mixture was heated at 90° C. and a solution of4-bromo-2,3-dihydro-1H-inden-1-one (50.0 g, 236 mmol) in anhydroustoluene was added dropwise over 90 min. The reaction mixture was thenstirred at 90° C. for 4 h and then overnight at 70° C. The crude(S,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamideIND INT-9 was used in the next experiment without purification. LCMS-ESI(m/z) calculated C₁₃H₁₈BrNOS: 315.0. found 316.0 [M+H]⁺, t_(R)=3.65 min.

(R,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamideIND INT-10 was prepared in an analogous fashion using(R)-2-methylpropane-2-sulfinamide.

(S)—N—((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide(IND INT-11)

To a stirred suspension of crude(S,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamideIND INT-9 in toluene (250 mL) under N₂ was added anhydrous THF (250 mL)and the reaction mixture was cooled to −78° C. Sodium borohydride (26.8g, 710 mmol) was added in four portions over 30 min (internaltemperature maintained below −65° C.). The reaction mixture was stirredat −78° C. for 30 min before it was warmed to room temperature over 1 hand continued to stir for additional 1 h. The reaction mixture wasfiltered through Celite pad to remove Ti salts. The filtrate was treatedwith EA (500 mL), saturated sodium potassium tartrate (200 mL), andbrine (50 mL) and the mixture stirred at room temperature overnight. Themixture was filtered through a celite pad and the filtrate dried overMgSO₄. The crude product was obtained by concentration to dryness gave46 g (61%) of(S)—N—((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamideIND INT-11 as an off-white solid which was used in the next experimentwithout purification. LCMS-ESI (m/z) calculated C₁₃H₁₆BrNOS: 313.0.found 314.0 [M+H]⁺, t_(R)=3.84 min.

(R)—N—((R)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamideIND INT-12 was prepared in an analogous fashion using(R,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamideIND INT-10.

(S)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride (IND INT-13)

To a stirred suspension of crude(S)—N—((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamideIND INT-11 (46 g, 145 mol) in MeOH (100 mL) was added 4N HCl in dioxane(109 mL) and the yellow suspension was stirred at room temperature for 3h. The crude reaction was diluted with MeOH (100 mL) and filtered. Thefiltrate was concentrated and the solid obtained was dispersed intoacetonitrile (600 mL) and refluxed for 90 min. The suspension was cooledto 0° C. and the solid filtered to produce 25 g of (69%)(S)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride IND INT-13 whichwas used in the next step without purification. LCMS-ESI (m/z)calculated for C₉H₁₀BrN: 211.09. found 197.0 [M-NH₂]⁺, t_(R)=1.76 min.¹H NMR (400 MHz, DMSO) δ 8.76 (s, 2H), 7.71 (d, J=7.5 Hz, 1H), 7.57 (d,J=7.9 Hz, 1H), 7.26 (t, J=7.7 Hz, 1H), 4.80 (s, 1H), 3.06 (ddd, J=16.9,8.9, 5.2 Hz, 1H), 2.93-2.76 (m, 1H), 2.57-2.39 (m, 1H), 2.11-1.92 (m,1H); ¹³C NMR (101 MHz, DMSO) δ 144.12, 141.60, 131.71, 129.02, 124.54,119.29, 55.30, 31.52, 29.10.

(R)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride IND INT-14 wasprepared in an analogous fashion using(R)—N—((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamideIND INT-12.

(S)-tert-butyl 4-bromo-2,3-dihydro-1H-inden-1-ylcarbamate (IND INT-15)

To crude (S)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride INDINT-13 (16.6 g, 66 mmol) in DCM (140 mL) at 0° C. was addedtriethylamine (14.8 g, 146 mmol) and di-tert-butyl dicarbonate (16.0 g,73 mmol). The reaction was stirred at room temperature overnight. Thereaction was diluted with DCM (50 mL) and washed with water and brine.The organic layers were dried over MgSO₄ and the product purified bycrystallization from 10% EA/hexanes to afford 14 g of (70%)(S)-tert-butyl 4-bromo-2,3-dihydro-1H-inden-1-ylcarbamate IND INT-15 asan off-white solid. LCMS-ESI (m/z) calculated for C₁₄H₁₈BrNO₂: 312.2.found 197.0 [M-NH₂Boc]⁺, t_(R)=3.94 min. ¹H NMR (400 MHz, CDCl₃) δ 7.38(d, J=7.9 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.08 (t, J=7.7 Hz, 1H), 5.25(dd, J=15.9, 7.9 Hz, 1H), 4.78 (d, J=7.6 Hz, 1H), 2.99 (ddd, J=16.5,9.0, 3.4 Hz, 1H), 2.81 (dt, J=16.5, 8.2 Hz, 1H), 2.70-2.36 (m, 1H),1.94-1.71 (m, 1H), 1.47 (d, J=5.2 Hz, 9H). ¹³C NMR (101 MHz, CDCl₃) δ155.99, 146.13, 143.83, 131.35, 129.02, 123.41, 120.64, 80.10, 57.21,33.71, 31.82, 28.86; Chiral HPLC: (S)-tert-butyl4-bromo-2,3-dihydro-1H-inden-1-ylcarbamate was eluted using 2% IPA inhexanes: >99.9% ee, t_(R)=11.08 min.

(R)-tert-butyl 4-bromo-2,3-dihydro-1H-inden-1-ylcarbamate IND INT-16 wasprepared in an analogous fashion from(R)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride INDINT-14: >99.9% ee t_(R) for (R)-enantiomer=9.98 min.

(S)-tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate(IND INT-17)

A solution of (S)-tert-butyl 4-bromo-2,3-dihydro-1H-inden-1-ylcarbamateIND INT-15 (13.1 g, 42 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (11.7 g, 46mmol), and potassium acetate (12.3 mg, 125 mmol) in anhydrous1,4-dioxane (100 mL) was degassed by passing N₂ through the solution for30 min before the addition of PdCl₂(dppf).CH₂Cl₂ (6.8 g, 8.3 mmol). Thereaction mixture was heated at 85° C. for 8 h. The solvent was removedunder vacuum and the residue was dissolved in EA (500 mL) and filteredthrough celite. The filtrate was washed with water and brine, dried overMgSO₄, and purified by chromatography (EA/hexanes) to afford 13 g (87%)of (S)-tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamateIND INT-17 as white solid. LCMS-ESI (m/z) calculated for C₂₀H₃₀BNO₄:359.2. found 382.2 [M+Na]⁺, t_(R)=4.26 min. ¹H NMR (400 MHz, CDCl₃) δ7.66 (d, J=7.3 Hz, 1H), 7.39 (d, J=7.5 Hz, 1H), 7.19 (t, J=7.4 Hz, 1H),5.14 (dd, J=15.8, 7.8 Hz, 1H), 4.69 (d, J=8.7 Hz, 1H), 3.23 (ddd,J=17.0, 8.8, 3.5 Hz, 1H), 2.94 (dt, J=16.6, 8.2 Hz, 1H), 2.53 (ddd,J=11.4, 8.0, 3.9 Hz, 1H), 1.73 (ddd, J=16.4, 12.8, 8.6 Hz, 1H), 1.46 (s,9H), 1.36-1.25 (m, 12H). ¹³C NMR (101 MHz, CDCl₃) δ 156.21, 150.64,143.43, 135.37, 127.25, 126.43, 83.95, 79.78, 56.19, 34.60, 31.57,28.88, 25.37, 25.34.

(R)-tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamateIND INT-18 was prepared in an analogous fashion using (R)-tert-butyl4-bromo-2,3-dihydro-1H-inden-1-ylcarbamate IND INT-16.

General Procedure 4: Coupling of Heterocyclic Bromides to Indane Amine

A reaction pressure flask was charged sequentially with the heterocyclicbromide (1 eq), (R)- or (S)-Boc-protected indane amine (1 eq), DME:H₂O(3:1, 0.07 M) and potassium carbonate (3 eq). The mixture was degassedby bubbling N₂ gas through the stirring solution for 20 min. ThenPd(PPh₃)₄ (0.07 eq) was added and the mixture was degassed foradditional 5 min. The reaction flask was capped tightly and the mixturewas heated at 85° C. for 12-24 h. The reaction was cooled to roomtemperature, diluted with water (2× volume), and stirred for 30 min. Theresulting solid was filtered, washed with hexanes, and dried under highvacuum. The crude product was purified by silica gel columnchromatography (EA/hexanes) or used in the next experiment withoutpurification.

(S)-tert-butyl(4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate

Prepared using General Procedure 4. A suspension of5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3 (1.5 g,5.3 mmol), (S)-tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamateIND INT-17 (1.9 g, 5.3 mmol) and potassium carbonate (2.2 g, 16 mmol) inDME:H₂O (3:1, 70 mL) was degassed with N₂ for 20 min before the additionof Pd(PPh₃)₄ (0.43 g, 0.3 mmol). The mixture was degassed with N₂ for anadditional 5 min and the suspension was heated under N₂ at 85° C. for 12h. Upon cooling, the reaction mixture was diluted with water (150 mL)and the mixture stirred for 30 min. The resulting solid was filtered,washed with water, and dried under high vacuum to afford 2.3 g (100%) ofcrude (S)-tert-butyl(4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamateas light brown solid which was used in the next experiment withoutpurification. LCMS-ESI (m/z) calculated for C₂₃H₂₁FN₄O₂S: 436.1. found459.1 [M+Na]⁺, t_(R)=4.19 min.

(R)-tert-butyl(4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamatewas prepared in an analogous fashion using (R)-tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamateIND INT-18.

(S)-tert-butyl(4-(2-(3-cyano-4-fluorophenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamate

Prepared using General Procedure 4. A solution of5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 (2.0 g, 7.0mmol), (S)-tert-butyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamateIND INT-17 (2.5 g, 7.0 mmol), potassium carbonate (2.9 g, 21 mmol) and a3:1 mixture of DME/H₂O (30 mL) was degassed with N₂ for 10 min beforethe addition of Pd(PPh₃)₄ (0.57 g, 0.005 mmol). The mixture was degassedwith N₂ for an additional 2 min and the suspension was heated undernitrogen at 80° C. for 12 h. Upon cooling, the reaction mixture wasdiluted with EA (20 mL) and washed with brine (20 mL). The combinedorganic layers were dried over MgSO₄, filtered, and concentrated. Thecrude product was purified by silica gel flash chromatography (30%EA/hexanes) to produce 3.0 g (83%) of (S)-tert-butyl(4-(2-(3-cyano-4-fluorophenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamateas a white solid. LCMS-ESI (m/z) calculated for C₂₄H₂₂FN₃O₂S: 435.5.found 436.1 [M+H]⁺, t_(R)=4.14 min. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (m,2H), 7.93 (s, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.32 (m, 3H), 5.26 (m, 1H),4.76 (d, J=8.4 Hz, 1H), 3.09 (m, 2H), 2.65 (ddd, J=12.5, 8.3, 4.6 Hz,1H), 1.84 (dq, J=12.9, 8.5 Hz, 1H), 1.48 (s, 9H).

(S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate

Prepared using General Procedure 2. To a solution of (S)-tert-butyl(4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(2.5 g, 5.7 mmol) in IPA (30 mL) was added sodium isopropoxide (0.61 g,7.4 mmol). The reaction mixture was heated at 60° C. for 4 h. Uponcooling, the mixture was concentrated to 50% volume and the suspensionwas cooled to 0° C. The resulting solid was filtered and dried underhigh vacuum to afford 1.14 g (42%) of (S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamateas off-white solid. LCMS-ESI (m/z) calculated for C₂₆H₂₈N₄O₃S: 476.2.found 477.2 (M+H). t_(R)=4.12 min. ¹H NMR (400 MHz, CDCl₃) δ 8.26-8.04(m, 2H), 7.82 (d, J=7.7 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.38 (d, J=7.6Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 5.38-5.08 (m, 1H), 4.94-4.62 (m, 1H),3.54-3.32 (m, 1H), 3.21 (s, 1H), 2.80-2.59 (m, 1H), 1.97-1.74 (m, 1H),1.52-1.35 (m, 15H). ¹³C NMR (101 MHz, CDCl₃) δ 166.93, 165.54, 161.59,155.65, 145.84, 142.05, 133.28, 128.71, 127.59, 126.64, 126.33, 122.72,115.54, 113.86, 103.69, 79.59, 72.50, 60.35, 55.73, 33.78, 31.27, 28.39,21.74.

(R)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate was prepared in an analogous fashion using (R)-tert-butyl(4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate.

(S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate

Prepared using General Procedure 2. To a solution of (S)-tert-butyl(4-(2-(3-cyano-4-fluorophenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(2.5 g, 5.7 mmol) in IPA (50 mL) was added sodium isopropoxide (0.61 g,7.4 mmol). The reaction mixture was heated at 60° C. for 4 h. Uponcooling, the mixture was concentrated to 50% volume and the suspensionwas cooled to 0° C. The resulting solid was filtered and dried underhigh vacuum to afford 2.66 g (98%) of (S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate. LCMS-ESI (m/z)calculated for C₂₇H₂₉N₃O₃S: 475.1. found 476.2 (M+H). t_(R)=4.30 min. ¹HNMR (400 MHz, CDCl₃) δ 8.19-8.05 (m, 2H), 7.89 (s, 1H), 7.43 (s, 1H),7.39-7.28 (m, 2H), 7.04 (d, J=8.9 Hz, 1H), 5.39-5.15 (m, 1H), 4.73 (s,2H), 3.20-2.94 (m, 2H), 2.69-2.57 (m, 1H), 1.94-1.77 (m, 1H), 1.49 (s,9H), 1.44 (d, J=6.1 Hz, 6H).

General Procedure 5: Preparation of Heterocyclic Indane Amines

To a stirred suspension of the (R)- or (S)-Boc protected indane amine (1eq) in 1,4-dioxane (0.2 M) was added 4N HCl in 1,4-dioxane (10 eq) andthe mixture was heated at 55° C. until completion of the reaction (3-5h). The reaction was cooled to room temperature and diluted with diethylether. The resulting solid was filtered and dried under vacuum to obtainthe pure product as the hydrochloride salt.

Compounds 4-6 and 71-72 were prepared by the sequential use of GeneralProcedures 4, 2, and 5.

(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride (Compound 4)

Prepared using General Procedure 5. To a stirred solution of(S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(1.1 g, 2.3 mmol) in 1,4-dioxane (10 mL) was added 4N HCl solution of in1,4-dioxane (10 mL). The reaction mixture was stirred at 55° C. for 2.5h. Upon cooling to 0° C., the reaction mixture was diluted with diethylether (100 mL) and the resulting solid was filtered and dried to afford980 mg (96%) of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 as off-white solid. LCMS-ESI (m/z) calculated forC₂₁H₂₀N₄OS, 376.1. found 377.1 (M+H). t_(R)=2.35 min. ¹H NMR (400 MHz,DMSO) δ 8.64-8.51 (m, 3H), 8.41 (d, J=2.3 Hz, 1H), 8.32 (dd, J=8.9, 2.4Hz, 1H), 7.99 (d, J=7.4 Hz, 1H), 7.84 (d, J=7.6 Hz, 1H), 7.59-7.49 (m,2H), 4.95 (dt, J=12.2, 6.1 Hz, 1H), 4.84 (s, 1H), 3.54-3.32 (m, 1H),3.30-3.15 (m, 1H), 2.65-2.53 (m, 1H), 2.12 (ddd, J=13.9, 5.6, 3.0 Hz,1H), 1.37 (dd, J=10.4, 6.1 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 166.61,166.11, 161.5, 143.05, 141.73, 134.16, 133.45, 129.74, 128.26, 127.84,126.47, 122.33, 115.79, 115.2, 102.53, 72.43, 54.75, 31.48, 30.12,21.74. Chiral HPLC:(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 was eluted using 30% EtOH in hexanes plus 0.1% DEA:99.0% ee, t_(R)=34.2 min.

(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2isopropoxybenzonitrile hydrochloride 5 was prepared in an analogousfashion using (R)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate: >99.9%ee, t_(R)=28.8 min.

(S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride (Compound 71)

Prepared using General Procedure 5. To a stirred solution of(S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(1.0 g, 2.1 mmol) in 1,4-dioxane (5 mL) was added 4N HCl solution in1,4-dioxane (5 mL). The reaction mixture was stirred at 55° C. for 2.5h. Upon cooling to 0° C., the reaction mixture was diluted with diethylether (50 mL) and the resulting solid was filtered, washed with ether(20 mL), and dried to afford 0.86 g (100%) of(S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride 71. LCMS-ESI (m/z) calculated for C₂₂H₂₁N₃OS: 375.1. found376.2 (M+H). t_(R)=2.45 min. ¹H NMR (400 MHz, DMSO) δ 8.64 (d, J=3.6 Hz,2H), 8.30 (d, J=2.3 Hz, 1H), 8.23 (dd, J=8.9, 2.4 Hz, 1H), 8.21 (s, 1H),7.70 (dd, J=7.6, 2.6 Hz, 2H), 7.45 (dd, J=8.4, 5.4 Hz, 2H), 4.91 (dt,J=12.2, 6.1 Hz, 1H), 4.85-4.58 (m, 1H), 3.36-3.21 (m, 1H), 3.21-3.04 (m,1H), 2.63-2.51 (m, 1H), 2.09 (td, J=8.3, 2.8 Hz, 1H), 1.43-1.28 (m, 6H).¹³C NMR (101 MHz, DMSO) δ 166.61, 166.11, 161.50, 143.05, 141.73,134.16, 133.45, 129.74, 128.26, 127.84, 126.47, 122.33, 115.79, 115.20,102.53, 72.43, 54.75, 31.48, 30.12, 21.74. Chiral HPLC:(S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride was eluted in 8% EtOH/hexanes: >99.9% ee, t_(R)=67.15 min(Chiral Method 1).

(R)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride 72 was prepared in an analogous fashion using(R)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate:99.0% ee, t_(R) for (R)-enantiomer=62.18 min.

General Procedure 6. Preparation of Indane Amides Via Acid Coupling

To the appropriate acid (1 eq) in DMF (0.05 M) was added HOBt (1.3 eq),and EDC (1.3 eq). The reaction was stirred at room temperature for 0.5 hor until the acid was fully activated. The (R)- or (S)-indane amine (1eq) was added in one portion and the reaction was stirred at roomtemperature for 12 h. The crude reaction mixture was subjected topreparative HPLC purification. Products that contain Boc protected amineside chains were further treated with 4N HCl in 1,4-dioxane and heated55° C. for 2 h. The reaction mixture was diluted with diethyl ether andfiltered to afford the desired products as the hydrochloride salts.

Compounds 7-13, 49, 73, 74, 77-86 were prepared using General Procedure6.

(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyacetamide(Compound 7)

Prepared using General Procedure 6. A solution of 2-hydroxyacetic acid(4 mg, 0.05 mmol), HOBt (8.8 mg, 0.06 mmol), EDC (12.5 mg, 0.06 mmol)and DIEA (15 mg, 0.11 mmol) in DMF (1 mL) was stirred for 30 min beforethe addition of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 in DMF (0.5 mL). The reaction mixture was stirred atroom temperature overnight. The crude reaction mixture was preparativeHPLC to produce 10 mg (50%) of(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyacetamide7 as white solid. LCMS-ESI (m/z) calculated for: C₂₃H₂₂N₄O₃S: 434.1.found 435.1 [M+H]⁺, t_(R)=3.11 min. ¹H NMR (400 MHz, CDCl₃) δ 8.19 (dd,J=8.9, 2.3 Hz, 1H), 8.12 (d, J=2.2 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.42(d, J=7.5 Hz, 1H), 7.34 (t, J=7.6 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 6.85(d, J=8.5 Hz, 1H), 5.71-5.46 (m, 1H), 4.76 (dt, J=12.2, 6.1 Hz, 1H),4.21 (s, 2H), 3.46 (ddd, J=17.0, 8.7, 3.6 Hz, 1H), 3.30-3.09 (m, 1H),2.69 (ddd, J=16.6, 8.3, 4.0 Hz, 1H), 2.08-1.80 (m, 2H), 1.46 (d, J=6.1Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 167.44, 166.23, 162.20, 145.53,142.82, 133.89, 133.79, 129.53, 128.28, 127.20, 126.93, 123.12, 116.03,114.38, 104.22, 73.06, 62.72, 54.46, 33.91, 31.98, 22.24.

(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyacetamide8 was prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydro-chloride 5.

(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyacetamide(Compound 73)

Prepared using General Procedure 6. A solution of 2-hydroxyacetic acid(2 mg, 0.02 mmol), HOBt (4.8 mg, 0.06 mmol), EDC (7.0 mg, 0.06 mmol) andDIEA (7.7 mg, 0.06 mmol) in DMF (1 mL) was stirred for 30 min before theaddition of(S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride 71 in DMF (0.5 mL). The reaction mixture was stirred atroom temperature overnight. The crude reaction mixture was subjected topreparative HPLC to produce 5 mg (58%) of((S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyacetamide73 as white solid. LCMS-ESI (m/z) calculated for: C₂₄H₂₃N₃O₃S: 433.2.found 434.1 [M+H]⁺, t_(R)=3.11 min.

General Procedure 7. Preparation of Indane Amides Via Acid Chlorides

To a stirred solution of (R)- or (S)-indane amine hydrochloride (1 eq)in anhydrous DCM (0.03 M) was added triethylamine (3 eq) followed by theappropriate acid chloride (1.5 eq). The reaction mixture was stirredovernight at room temperature. The solvent was evaporated and theproduct was purified by preparative HPLC.

Compounds 14, 15, 75, 76, 87, and 88 were prepared using GeneralProcedure 7.

(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)acetamide(Compound 14)

Prepared using General Procedure 7: To a stirred solution of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 (15 mg, 0.03 mmol) in anhydrous DCM (1 mL) was addedtriethylamine (11 mg, 0.1 mmol) followed by acetyl chloride (4.2 mg,0.05 mmol) and the reaction mixture was stirred at room temperatureovernight. The solvent was evaporated and the crude mixture purified bypreparative HPLC to afford(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)acetamide14. LCMS-ESI (m/z) calculated for: C₂₃H₂₂N₄O₂S: 418.2. found 419.3[M+H]⁺, t_(R)=3.34 min. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (dd, J=8.9, 2.3Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.45 (d, J=7.5Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.08 (d, J=9.0 Hz, 1H), 5.83 (d, J=8.4Hz, 1H), 5.57 (q, J=7.9 Hz, 1H), 4.76 (dt, J=12.2, 6.1 Hz, 1H), 3.46(ddd, J=17.1, 8.8, 3.8 Hz, 1H), 3.28-3.15 (m, 1H), 2.75-2.62 (m, 1H),2.07 (s, 3H), 1.98-1.80 (m, 1H), 1.46 (d, J=6.1 Hz, 6H). ¹³C NMR (101MHz, CDCl₃) δ 170.36, 167.43, 166.14, 162.16, 145.92, 142.83, 133.89,133.77, 129.44, 128.23, 127.18, 126.95, 123.21, 116.05, 114.36, 104.23,73.03, 55.00, 34.03, 31.95, 23.92, 22.24.

(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)acetamide15 was prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 5.

(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-methoxyacetamide(Compound 76)

Prepared using General Procedure 7: To a stirred solution of(S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride 71 (15 mg, 0.03 mmol) in anhydrous DCM (1 mL) was addedtriethylamine (11 mg, 0.1 mmol) followed by 2-methoxyacetyl chloride(11.8 mg, 0.1 mmol) and the reaction mixture was stirred at roomtemperature overnight. The solvent was evaporated and the crude mixturewas purified by preparative HPLC to afford(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-methoxyacetamide76. LCMS-ESI (m/z) calculated for: C₂₅H₂₅N₃O₃S: 447.2. found 448.1[M+H]⁺, t_(R)=3.70 min.

General Procedure 8. Preparation of Indane Carbamates

To a stirred solution of (R)- or (S)-indane amine (1 eq) in DCM (0.03M)was added TEA (3 eq) and the appropriate carbonochloridate (1.5 eq) atroom temperature. The reaction was stirred at room temperature for 4 h.The solvent was evaporated and the pure product isolated byprecipitation with water or preparative HPLC.

Compounds 16, 68, 89, and 90 were prepared using General Procedure 8.

(S)-methyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(Compound 16)

Prepared using General Procedure 8. To a stirred solution of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 (15 mg, 0.03 mmol) and TEA (11 mg, 0.1 mmol) in DCM (1mL) was added methyl chloroformate (10 mg, 0.1). The reaction mixturewas stirred at room temperature for 16 h. The solvent was evaporated andwater (2 mL) was added. The resulting solid was filtered, washed withwater, and dried under high vacuum to afford 12 mg (92%) of (S)-methyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate16 as white solid. LCMS-ESI (m/z) calculated for C₂₃H₂₂N₄O₃S: 434.1.found 435.3 [M+H]⁺, t_(R)=3.69 min.

(S)-methyl(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamate(Compound 90)

Prepared using General Procedure 8. To a stirred solution of(S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride 71 (15 mg, 0.03 mmol) and TEA (11 mg, 0.1 mmol) in DCM (1mL) was added methyl chloroformate (10 mg, 0.1). The reaction mixturewas stirred at room temperature for 16 h. The solvent was evaporated andwater (2 mL) was added. The resulting solid was filtered, washed withwater, and dried under high vacuum to afford 6 mg (51%) of (S)-methyl(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamate90 as white solid. LCMS-ESI (m/z) calculated for C₂₄H₂₃N₃O₃S: 433.2.found 434.1 [M+H]⁺, t_(R)=3.86 min.

General Procedure 9. Alkylation of Indane Amines

To a solution of the (R)- or (S)-indane amine in CH₃CN (0.2 M) was addedK₂CO₃ (3 eq) and the appropriate alkyl halide (1.2 eq). In some casesTEA (3 eq) and DMF (0.1 M) was used. The mixture was heated at 80-95° C.until the starting material was consumed or di-alkylation of the aminebecomes prevalent. If necessary, additional alkyl halide is added todrive the reaction. The reaction mixture was filtered to removeinorganic solids and concentrated, re-suspended in EA and washed withwater. The organic layer is dried and concentrated, then purified bychromatography (MeOH/DCM) or preparative HPLC to provide the desiredproduct. TBS-protected alcohols were deprotected using 4N HCl.

Compounds 17-20 and 91-95 were prepared using General Procedure 9.

(R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-M-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile

Prepared using General Procedure 9. To a suspension of(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 5 (50 mg, 0.12 mmol) in anhydrous DMF (5 mL) was added TEA(36.7 mg, 0.36 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (34.6mg, 0.14 mmol). The solution was stirred at 95° C. After 16 h more(2-bromoethoxy)(tert-butyl)dimethylsilane (34.6 mg, 0.14 mmol) was addedand heating continued for 12 h. Water (5 mL) was added and the reactionmixture was extracted with EA (2×5 mL). The organic layers were washedwith brine, dried, and purified by column chromatography (EA/hexanes) toafford 10 mg (15%) of(R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile.LCMS-ESI (m/z) calculated for: C₂₉H₃₈N₄O₂SSi: 534.3. found 535.3 [M+H]⁺,t_(R)=3.08 min.

(S)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilewas prepared in an analogous fashion using(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4.

(R)-5-(5-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile(Compound 17)

To(R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile(10 mg, 0.018 mmol), in 1,4-dioxane (1.5 mL) was added 4N HCl indioxanes (0.5 mL). The mixture was stirred at room temperature for 3 hand solvent was evaporated. The crude material was purified by apreparative HPLC to afford 7 mg (90%) of(R)-5-(5-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile17. LCMS-ESI (m/z) calculated for: C₂₃H₂₄N₄O₂S: 420.2. found 421.2[M+H]⁺, t_(R)=2.38 min. 1H NMR (400 MHz, CDCl₃) δ 8.19 (dd, J=8.9, 2.3Hz, 1H), 8.15 (d, J=2.2 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.88 (d, J=7.7Hz, 1H), 7.48 (t, J=7.7 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 4.94 (d, J=4.2Hz, 1H), 4.76 (dt, J=12.2, 6.1 Hz, 1H), 3.89 (d, J=16.3 Hz, 2H),3.68-3.20 (m, 2H), 3.20-2.89 (m, 2H), 2.72-2.53 (m, 2H), 2.65-2.53 (m,1H), 2.49-2.27 (m, 1H), 1.44 (d, J=6.1 Hz, 6H).

(S)-5-(5(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxy-benzonitrile18 was prepared in an analogous fashion using(S)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile.

(S)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile

Prepared using General Procedure 9. To a suspension of(S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride 71 (25 mg, 0.06 mmol) in anhydrous DMF (2 mL) was addedTEA (7.3 mg, 0.36 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane(6.9 mg, 0.14 mmol). The solution was stirred at 100° C. for 48 hours.The reaction was diluted with EA (10 mL), washed with water and brineand dried. Concentration and purification by column chromatography(EA/hexanes) gave 29 mg (90%) of(S)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrileas a dark gray solid. LCMS-ESI (m/z) calculated for: C₃₀H₃₉N₃O₂SSi:533.3. found 534.3 [M+H]⁺, t_(R)=3.22 min.

(R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-thiazol-2-yl)-2-isopropoxybenzonitrilewas prepared in an analogous fashion using(R)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride 72.

(S)-5-(5-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile(Compound 92)

To a solution of(S)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile(10 mg, 0.018 mmol) in ether (1 mL) was added 2N HCl in ether (0.1 mL).The mixture was stirred at room temperature for 12 h and solvent wasevaporated. The crude material was purified by a preparative HPLC toafford 6 mg (80%) of(S)-5-(5-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile92. LCMS-ESI (m/z) calculated for: C₂₄H₂₅N₃O₂S: 419.2. found 420.2[M+H]⁺, t_(R)=2.43 min.

(R)-5-(5-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile91 was prepared in an analogous fashion using(R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile.

(S)-methyl2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate

Prepared using General Procedure 9. To a suspension of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 (150 mg, 0.36 mmol) in CH₃CN (5 mL) was added K₂CO₃(150.9 mg, 1.09 mmol) and methyl 2-bromoacetate (67 mg, 0.43 mmol). Thesuspension was stirred at 80° C. After 6 h more methyl 2-bromoacetate(6.7 mg, 0.043 mmol) was added and heating continued for 12 h. Thereaction mixture was filtered and concentrated. The residue wasre-suspended in EA (15 mL), washed with water and brine, dried andconcentrated. The product was purified by a silica gel columnchromatography (MeOH/DCM) to afford 146 mg (90%) of (S)-methyl2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetateas white solid. LCMS-ESI (m/z) calculated for C₂₄H₂₄N₄O₃S: 448.2. found449.1 [M+H]⁺, t_(R)=2.48 min.

(R)-methyl2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetatewas prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 5.

(S)-methyl2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate

To a solution of (S)-methyl2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate(146 mg, 0.35 mmol) in DCM (2 mL) was added di-tert-butyl dicarbonate(85.3 mg, 0.39 mmol) and reaction was stirred at room temperature for 16h. Reaction was diluted with DCM (10 mL) and washed with NaHCO₃, water,and brine. The product was purified by a silica gel columnchromatography (EA/hexanes) to afford 118 mg (66%) of (S)-methyl2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetateas white solid. LCMS-ESI (m/z) calculated for C₂₉H₃₂N₄O₅S: 548.2. foundno M⁺, t_(R)=4.19 min.

(R)-methyl2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetatewas prepared in an analogous fashion using (R)-methyl2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate.

(S)-2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid

To a stirred solution of (S)-methyl2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate(120 mg, 0.21 mmol) in MeOH (2 mL) was added 6N solution of sodiumhydroxide (180 μL) and the mixture was stirred at room temperature forovernight. The solvent was evaporated and the residue was dissolved inwater (5 mL) and acidified with 1N HCl. The mixture was extracted withEA (3×5 mL) and the organic layers washed with brine, dried over MgSO₄,and concentrated to afford 108 mg (92%) of(S)-2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1yl)amino)aceticacid as white solid which was used in the next experiments withoutpurification. LCMS-ESI (m/z) calculated for C₂₈H₃₀N₄O₅S: 534.2. found noM⁺, t_(R)=3.81 min.

(R)-2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1yl)amino)aceticacid was prepared in an analogous fashion using (R)-methyl2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate.

(S)-methyl2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate(Compound 99)

Prepared using General Procedure 9. To a suspension of(S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride 71 (150 mg, 0.36 mmol) in CH₃CN (5 mL) was added K₂CO₃(150.9 mg, 1.09 mmol) and methyl 2-bromoacetate (66 mg, 0.43 mmol). Thesuspension was stirred at 80° C. for 16 h. The reaction mixture wasfiltered and concentrated. The residue was re-suspended in EA (15 mL),washed with water and brine, dried and concentrated. The product waspurified by a silica gel column chromatography (EA/hexanes) to afford 76mg (47%) of (S)-methyl2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetateas white solid. LCMS-ESI (m/z) calculated for C₂₅H₂₅N₃O₃S: 447.2. found448.2 [M+H]⁺, t_(R)=2.57 min. ¹H NMR (400 MHz, CDCl₃) δ 8.23-8.01 (m,2H), 7.90 (s, 1H), 7.41 (dd, J=21.0, 7.4 Hz, 1H), 7.29 (dd, J=9.8, 5.2Hz, 1H), 7.04 (d, J=8.9 Hz, 1H), 7.04 (d, J=8.9 Hz, 1H), 4.74 (dt,J=12.1, 6.1 Hz, 1H), 4.33 (t, J=6.1 Hz, 1H), 3.76 (d, J=4.8 Hz, 3H),3.55 (s, 2H), 3.24 (ddd, J=15.8, 8.2, 5.6 Hz, 1H), 3.05-2.86 (m, 1H),2.47-2.25 (m, 2H), 2.02-1.84 (m, 1H), 1.53-1.36 (m, 6H). ¹³C NMR (101MHz, CDCl₃) δ 173.14, 164.87, 161.08, 146.06, 141.45, 141.28, 138.20,132.13, 131.96, 128.08, 127.98, 127.56, 126.77, 124.66, 116.17, 114.01,103.76, 72.55, 62.94, 52.19, 48.53, 32.99, 31.34, 22.04.

(R)-methyl2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetatewas prepared in an analogous fashion using(R)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrilehydrochloride 72.

(S)-methyl2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate

To a solution of (S)-methyl2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate(76 mg, 0.17 mmol) in DCM (1 mL) was added di-tert-butyl dicarbonate(44.5 mg, 0.20 mmol) and reaction was stirred at room temperature for 16h. Reaction was diluted with DCM (10 mL) and washed with NaHCO₃, water,brine and then dried. Concentration of the filtrate gave 90 mg (96%) of(S)-methyl2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetateas white solid. LCMS-ESI (m/z) calculated for C₃₀H₃₃N₃O₅S: 547.21. foundno M⁺, t_(R)=4.42 min.

(R)-methyl2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetatewas prepared in an analogous fashion using (R)-methyl2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate.

(S)-2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid

To a stirred solution of (S)-methyl2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate(120 mg, 0.22 mmol) in MeOH (2 mL) was added 6N sodium hydroxide (180μL) and the mixture was stirred at room temperature for overnight. Thesolvent was evaporated and the residue was dissolved in water (5 mL) andacidified with 1N HCl. The mixture was extracted with EA (3×5 mL) andthe organic layers washed with brine, dried over MgSO₄, and concentratedto afford 110 mg (94%) of(S)-2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid as white solid which was used in the next experiments withoutpurification. LCMS-ESI (m/z) calculated for C₂₉H₃₁N₃O₅S: 533.2. found534.2 [M+H]⁺, t_(R)=3.92 min.

(R)-2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid was preparedin an analogous fashion using (R)-methyl2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate.

General Procedure 10. Preparation of Indane Amino Amides

To the Boc-protected (R)- or (S)-indane aminoacid (1 equivalent) in DMF(2 M) was added HOBt (1.35 eq) and EDC (1.35 eq) and the reaction wasstirred at room temperature for 60 min. The appropriate amine (1.1 eq)was added and the reaction was stirred at room temperature for 2 h. TheBoc-protected amino amide was precipitated out of water or extractedwith EA and dried over MgSO₄. The product was purified byrecrystallization or preparative HPLC. The resulting solid was heated in4M HCl/dioxane at 50° C. until the reaction was complete. The productwas precipitated as the hydrochloride salt by the addition of diethylether.

Compounds 21-25, 39, and 98, 100-108 were prepared using GeneralProcedure 10.

(S)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-N,N-dimethylacetamidehydrochloride (Compound 21)

Prepared using General Procedure 10. To(S)-2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1yl)amino)acetic(25 mg, 0.04 mmol) was added HOBt (9.4 mg, 0.07 mmol) and EDC (13.3 mg,0.07 mmol) in anhydrous DMF (1 mL) and the reaction mixture stirred atroom temperature for 60 min. Dimethyl amine (2.3 mg, 0.05 mmol) wasadded and the mixture was stirred at room temperature for 12 h. Thecrude reaction was purified by preparative HPLC purification to providethe Boc-product amido amide as white solid. This material was treatedwith 4N HCl in dioxane at 50° C. for 2 h. The reaction mixture wasdiluted with diethyl ether (5 mL), and the resulting solid collected toafford 10 mg (46% over two steps) of(S)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-N,N-dimethylacetamidehydrochloride 21. LCMS-ESI (m/z) calculated for C₂₅H₂₇N5O₂S: 461.2.found 462.1 [M+H]⁺, t_(R)=3.90 min.

(R)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-N,N-dimethylacetamidehydrochloride 22 was prepared in an analogous fashion using(R)-2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1yl)amino)acetic.

5-(5-((S)-1-((2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile(Compound 104)

Prepared using General Procedure 10. To(S)-2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid (12 mg, 0.02 mmol) and HOBt (4.5 mg, 0.03 mmol) was added EDC (6.4mg, 0.03 mmol) in anhydrous DMF (1 mL) and the reaction mixture stirredat room temperature for 60 min. (S)-pyrrolidin-3-ol (2.3 mg, 0.02 mmol)was added and the mixture was stirred at room temperature for 12 h. Thecrude reaction was purified by preparative HPLC purification to providethe Boc-product amido amide as white solid. This material was treatedwith 4N HCl in dioxane at 50° C. for 2 h. The reaction mixture wasdiluted with diethyl ether (5 mL), and the resulting solid collected toafford 5 mg (50% over two steps) of5-(5-((S)-1-((2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 104. LCMS-ESI (m/z)calculated for C₂₈H₃₀N₄O₃S: 502.2. found 503.2 [M+H]⁺, t_(R)=3.77 min.

5-(5-((R)-1-((2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 102 was prepared inan analogous fashion using(R)-2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid.

(R)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid (Compound 27)

To a stirred solution of(R)-2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid (20 mg, 0.03) mmol in 1,4-dioxane (0.5 mL) was added 4N HCl in1,4-dioxane (0.2 mL). The mixture was stirred at 50° C. for 2 h beforeit was concentrated and triturated with ether to afford 13 mg of(R)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid as yellow-green solid. LCMS-ESI (m/z) calculated for C₂₃H₂₂N₄O₃S:434.14. found 435.2 [M+H]⁺, t_(R)=2.51 min.

(S)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid 26 was in prepared in similar fashion using(S)-2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid.

(R)-2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid (Compound 96)

To (R)-methyl2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate(100 mg, 0.22 mmol) in ethanol was added 2N NaOH (1.1 mL) and themixture stirred at room temperature for 12 h. The solvent was evaporatedand the residue dissolved in water and acidified with 1N HCl. Theresulting solid was filtered and dried to give 60 mg (63%) of(R)-2-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid 96 as yellow-green solid. LCMS-ESI (m/z) calculated forC₂₄H₂₃N₃O₃S: 433.1. found 434.2 [M+1]]⁺, t_(R)=2.61 min.

(S)-2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)aceticacid 97 was prepared in an analogous fashion using (S)-methyl2-((4(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate.

General Procedure 11. Reductive Aminations of Indane Amines.

To a solution of the primary or optionally substituted secondary (R)- or(S)-indane amine (1 eq) in MeOH (0.01 M) was added acetic acid (0.01 eq)and the appropriate aldehyde (1.1 eq). The reaction was stirred at25-50° C. until imine formation was complete (2-18 h). Sodiumborohydride or sodium triacetoxyborohydride (10 eq) was added and thereaction was stirred at room temperature until reduction was complete(2-8 h). The solvent was evaporated and the residue partitioned betweenNaHCO₃ and EA. The organic layer was collected, dried and purified bypreparative HPLC.

Compounds 28-30, 109 and 110 were prepared using General Procedure 11.

(S)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile(Compound 28)

Prepared using General Procedure 11. To(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 (25 mg, 0.06 mmol) and 1H-imidazole-2-carbaldehyde (6.4mg, 0.06 mmol) in anhydrous MeOH (1 mL) was added acetic acid (1 drop).The solution was stirred at 55° C. for 3 h before cooling to roomtemperature and the addition of NaBH₄ (4.6 mg, 0.12 mmol). The mixturewas stirred at room temperature for 12 h. The reaction mixture wasquenched with water (0.5 mL) and partitioned between EA (5 mL) and water(5 mL). The organic layers washed with water and brine, and the productpurified by preparative HPLC to afford 22 mg (81%) of(S)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile28 as half-white solid. LCMS-ESI (m/z) calculated for C₂₅H₂₄N₆OS: 456.2.found 457.2 [M+H]⁺, t_(R)=2.38 min.

(R)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile29 was prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 5.

(R)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile(Compound 109)

Prepared using General Procedure 11. To(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 72 (20 mg, 0.05 mmol) and 1H-imidazole-2-carbaldehyde (7mg, 0.07 mmol) in anhydrous MeOH (0.5 mL) was added acetic acid (1drop). The solution was stirred at 55° C. for 3 h before cooling to roomtemperature and the addition of NaBH₄ (37.8 mg, 0.1 mmol). The mixturewas stirred at room temperature for 12 h. The reaction mixture wasquenched with water (0.5 mL) and partitioned between EA (5 mL) and water(5 mL). The organic layers washed with water and brine, and the productpurified by preparative HPLC to afford 17 mg (77%) of(R)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile109. LCMS-ESI (m/z) calculated for C₂₆H₂₅N₅OS: 455.2. found 456.2[M+H]⁺, t_(R)=2.53 min.

(S)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile110 was prepared in an analogous fashion using(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 71.

(S)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)benzonitrile(Compound 31)

To a stirred solution of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 (25 mg, 0.06 mmol) and DIEA (32 mg, 0.24 mmol) in DMA (1mL) was added (methylsulfonyl)ethene (20 mg, 0.18 mmol). The reactionmixture was heated at 90° C. for 24 h. The solvent was evaporated andthe product purified by preparative HPLC to afford 9 mg (31%) of(S)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)benzonitrile31 as half-white solid. LCMS-ESI (m/z) calculated for C₂₄H₂₆N₄O₃S₂:482.1. found 483.1 [M+H]⁺, t_(R)=2.49 min.

(R)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)benzonitrile32 was prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 5.

(S)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)benzonitrile(Compound 221)

To a stirred solution of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 71 (60 mg, 0.15 mmol) and DIEA (32 mg, 0.24 mmol) in1,4-dioxane (0.5 mL) was added (methylsulfonyl)ethene (92 mg, 0.88mmol). The reaction mixture was heated at 90° C. for 24 h. The reactionwas diluted with DCM (5 mL) and washed with saturated aqueous ammoniumchloride (2×5 mL) and saturated aqueous sodium bicarbonate (2×5 mL) andthen dried. The crude reaction was purified by a silica gel column(MeOH/DCM) to yield 44 mg (61%) of(S)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)benzonitrile221 as brown liquid. LCMS-ESI (m/z) calculated for C₂₅H₂₇N₃O₃S₂: 481.1.found 482.1 [M+H]⁺, t_(R)=2.49 min. ¹H NMR (400 MHz, CDCl₃) δ 8.19-8.08(m, 2H), 7.92 (s, 1H), 7.46 (dd, J=7.4, 0.9 Hz, 1H), 7.33 (dt, J=14.9,7.3 Hz, 2H), 7.06 (d, J=8.9 Hz, 1H), 5.31 (s, 1H), 4.75 (dt, J=12.2, 6.1Hz, 1H), 4.35 (t, J=6.6 Hz, 1H), 3.41-3.15 (m, 5H), 3.10-2.96 (m, 4H),2.57-2.45 (m, 1H), 1.93 (ddd, J=12.8, 6.2, 1.7 Hz, 1H), 1.46 (d, J=6.1Hz, 6H).

(R)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)benzonitrile220 was prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 72.

General Procedure 12. Preparation of Indane Sulfonamides via SulfonylChlorides

To a stirred solution of (R)- or (S)-indane amine (1 eq) in DCM (0.08M)was added TEA (3 eq) and the appropriate sulfonyl chloride (1.5 eq.) atroom temperature. The reaction was stirred at room temperature for 18 h.The solvent was evaporated and the pure product isolated afterpreparative HPLC purification.

Compounds 33-36 and 111-120 were prepared using General Procedure 12.

(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide(Compound 33)

Prepared using General Procedure 12. To a stirred solution of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 (20 mg, 0.04 mmol) and TEA (14.7 mg, 0.14 mmol) in DCM(2 mL) was added methane sulfonylchloride (8.3 mg, 0.07 mmol) and themixture was stirred at room temperature for 16 h. The solvent wasevaporated and the residue purified by preparative HPLC to afford 12 mg(55%) of(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide33 as white solid. LCMS-ESI (m/z) calculated for C₂₂H₂₂N₄O₃S₂: 454.1.found 455.1 [M+H]⁺, t_(R)=3.48 min.

(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide34 was prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 5.

(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide(Compound 111)

Prepared using General Procedure 12.(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 72 (60 mg, 0.15 mmol) and TEA (0.06 mL, 0.4 mmol) in DCM(0.5 mL) was added methane sulfonylchloride (8.3 mg, 0.07 mmol) at 0° C.and the reaction mixture was stirred at room temperature for 16 h. Themixture was diluted with DCM (5 mL) and washed with aqueous ammoniumchloride, and brine. The crude material was purified by silica gelcolumn chromatography (MeOH/DCM) to afford 39 mg (58%) of(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)methane sulfonamide 111 as white solid. LCMS-ESI (m/z) calculated forC₂₃H₂₃N₃O₃S₂: 453.1. found 454.1 [M+H]⁺, t_(R)=3.64 min.

(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide112 was prepared in an analogous fashion using(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 71.

(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide

To a stirred solution of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 (40 mg, 0.5 mmol) and TEA (49 mg, 0.48 mmol) in DCM (2mL) was added 2-chloroethanesulfonyl chloride (79 mg, 0.48 mmol) at 0°C. The reaction was warmed to room temperature and stirred for 2 h. Thereaction was quenched by the addition of NaHCO₃. The product waspurified by chromatography (EA/hexane) to provide 30 mg (66%) of(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamideas yellow solid. LCMS-ESI (m/z) calculated for C₂₃H₂₂N4O₃S₂: 466.1.found 467.1 [M+H]⁺, t_(R)=3.63 min.

(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamidewas prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 5.

(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide

To(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 72 (0.5 g, 1.3 mmol) in DCM (10 mL) was added TEA (0.88mL, 6.3 mmol) followed by 2-chloroethanesulfonyl chloride (0.4 mL, 163mmol) at 0° C. and the reaction was stirred at room temperatureovernight. During this time additional reagents TEA (0.2 mL) and2-chloroethanesulfonyl chloride (0.15 mL) were added to drive thereaction to completion. The reaction mixture was concentrated and thecrude residue was purified by a silica gel column (EA/hexanes) to afford378 mg of(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamideas fine yellow powder. LCMS-ESI (m/z) calculated for C₂₄H₂₃N₃O₃S₂:465.12. found 466.1 [M+H]⁺, t_(R)=3.82 min. ¹H NMR (400 MHz, CDCl₃) δ8.10 (s, 2H), 7.85 (s, 1H), 7.48-7.26 (m, 3H), 7.01 (d, J=7.3 Hz, 1H),6.64 (dd, J=16.5, 9.8 Hz, 1H), 6.33 (d, J=16.5 Hz, 1H), 5.97 (d, J=9.8Hz, 1H), 4.90 (d, J=7.3 Hz, 1H), 4.77-4.46 (m, 2H), 3.32-2.83 (m, 2H),2.64 (s, 1H), 2.02-1.84 (m, 1H), 1.40 (t, J=5.8 Hz, 6H).

(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)ethane sulfonamide was prepared in an analogous fashion using(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 71.

General Procedure 13. Preparation of Indane Sulfonamides via MichaelAddition

To a stirred solution of the (R)- or (S)-indane vinyl sulfonamide (1 eq)in DMF (0.1M) was added the appropriate amine (10 eq) The reaction wasstirred at 80° C. for 18 h. The product was purified by preparativeHPLC.

Compounds 37-38 and 121-153 were prepared using General Procedure 13.

N—((S)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)ethanesulfonamide(Compound 37)

Prepared using General Procedure 13. To a solution of(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide(40 mg, 0.5 mmol) in DMF (0.5 mL) was added (R)-pyrrolidin-3-ol (18.7mg, 0.21 mmol) and the reaction was heated to 80° C. for 18 h. Theproduct was purified by preparative HPLC to give 30 mg (56%) ofN—((S)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)ethanesulfonamide37 as an off-white solid. LCMS-ESI (m/z) calculated for C₂₇H₃₁N₅O₄S₂:553.2. found 554.2 [M+H]⁺, t_(R)=2.52 min.

N—((R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)ethanesulfonamide38 was prepared in an analogous fashion using(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide.

N—((R)-4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypiperidin-1-yl)ethanesulfonamide(Compound 143)

Prepared using General Procedure 13. To a solution of(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide(10 mg, 0.02 mmol) in DMF (0.5 mL) was added (R)-piperidin-3-olhydrochloride (20.6 mg, 0.15 mmol) and the reaction was heated to 80° C.for 18 h. The product was purified by preparative HPLC to give 10 mg(80%) ofN—((R)-4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypiperidin-1-yl)ethanesulfonamide143. LCMS-ESI (m/z) calculated for C₂₉H₃₄N₄O₄S₂: 566.2. found 567.2[M+H]⁺, t_(R)=2.62 min.

N—((S)-4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypiperidin-1-yl)ethanesulfonamide141 was prepared in an analogous fashion using(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide.

General Procedure 14. Preparation of Indane Sulfonamide Esters

To a stirred solution of (R)- or (S)-indane amine (1 eq) in DCM (0.2 M)was added the sulfonyl chloride (1.5 eq) at room temperature. For lessreactive or hindered sulfonyl chloride esters DIEA (2-3 eq) was added.The reaction was stirred at room temperature for 18 h. The crudereaction was partitioned between DCM and NaHCO₃. The organic layer wasdried over MgSO₄, concentrated, and purified by column chromatography.

Compounds 154-157 were prepared using General Procedure 14.

(S)-ethyl2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate

Prepared using General Procedure 14: To a stirred solution of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile4 (177 g, 0.47 mmol) and DIEA (182 mg, 1.4 mmol) in DCM (8 mL) was addedfreshly prepared ethyl-2-(chlorosulfonyl)acetate (131 mg, 0.7 mmol).After 45 min, the crude reaction was partitioned between DCM and NaHCO₃.The organic layer was dried over MgSO₄, concentrated, and purified bycolumn chromatography (EA/hexanes) to provide 75 mg (30%) of (S)-ethyl2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetateas light yellow solid. LCMS-ESI (m/z) calculated for C₂₅H₂₆N₄O₅S₂:526.1. found 527.1 [M+H]⁺, t_(R)=3.71 min. ¹H NMR (400 MHz, CDCl₃) δ8.16 (dd, J=8.9, 2.3 Hz, 1H), 8.09 (d, J=2.2 Hz, 1H), 7.76 (d, J=7.7 Hz,1H), 7.57 (d, J=7.6 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.03 (d, J=9.0 Hz,1H), 5.46 (t, J=7.9 Hz, 1H), 4.70 (dt, J=12.2, 6.1 Hz, 1H), 4.26-4.17(m, 2H), 4.00 (d, J=8.2 Hz, 2H), 3.49 (ddd, J=17.4, 9.5, 3.9 Hz, 1H),3.26-3.05 (m, 1H), 2.56 (ddd, J=12.9, 9.0, 4.4 Hz, 1H), 2.23-2.08 (m,1H), 1.41-1.37 (m, 6H), 1.28 (dd, J=11.7, 4.6 Hz, 3H).

(R)-ethyl2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetatewas prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile5.

(S)-methyl2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate(Compound 155)

Prepared using General Procedure 14: To a solution of(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile71 (20 mg, 0.04 mmol) in DCM (1 mL) was addedmethyl-2-(chlorosulfonyl)acetate (10 mg, 0.04 mmol). The reactionmixture was stirred at room temperature overnight and then diluted withDCM (5 mL), washed with saturated aq. NaHCO₃, and brine. The organiclayers were dried over MgSO₄, and the crude product purified by silicagel column chromatography to afford 11.2 mg (41%) of (S)-methyl2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate155 as orange-brown oil. LCMS-ESI (m/z) calculated for C₂₅H₂₅N₃O₅S₂:511.1. found 512.2 [M+H]⁺, t_(R)=3.71 min.

(R)-methyl2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate154 was prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile72.

General Procedure 15. Preparation of Indane Sulfonamide Acids

To a solution of (R)- or (S)-indane sulfonamide ester (1 eq) in 2:1EtOH/THF (0.2 M) was added 6N NaOH (5 eq) at room temperature. Thereaction was stirred at room temperature for 24 h. The crude reactionwas concentrated then partitioned between DCM/IPA and 1N HCl. Theorganic layer was dried over MgSO₄, concentrated, and isolated afterpreparative HPLC purification.

Compounds 40-41 and 158-161 were prepared using General Procedure 15.

(S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)aceticacid (Compound 40)

Prepared using General Procedure 15: To a stirred solution of (S)-ethyl2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (75 mg, 0.8 mmol) in MeOH (4 mL) was added 6N NaOH (0.12 mL).After 3 h, the crude reaction was concentrated then partitioned betweenDCM/IPA and 1N HCl. The organic layer was dried over MgSO₄ andconcentrated to give 43 mg (60%) of(S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)aceticacid 40 as light yellow solid. LCMS-ESI (m/z) calculated forC₂₃H₂₂N₄O₅S₂: 498.1. found 499.1 [M+H]⁺, t_(R)=3.34 min.

(R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)aceticacid 41 was prepared in an analogous fashion using (R)-ethyl2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate.

(S)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)aceticacid (Compound 159)

Prepared using General Procedure 15: To a stirred solution containing(S)-methyl2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (11.2 mg, 0.02 mmol) in MeOH (1 mL) was added 6N NaOH (100 uL).After 1 h, the crude reaction was concentrated and the product purifiedby preparative HPLC to give 5 mg (45%) of(S)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)aceticacid 159 as light yellow solid. LCMS-ESI (m/z) calculated forC₂₄H₂₃N₃O₅S₂: 497.1. found 498.1 [M+H]⁺, t_(R)=3.44 min.

(R)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)aceticacid 158 was prepared in an analogous fashion using (R)-methyl2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate.

General Procedure 16. Preparation of Indane Sulfonamide Amides

To a stirred solution of (R)- or (S)-indane sulfonamide acid (1 eq) inDCM (0.25 M) was added HATU (3 eq) and DIEA (2 eq). After 30 min, theamine was added and the reaction mixture stirred 18 h at roomtemperature. The reaction was quenched with water and purified bypreparative HPLC.

Compounds 42-44, 162, and 163 were prepared using General Procedure 16.

(R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide(Compound 43)

Prepared using General Procedure 16: To(R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)aceticacid (20 mg, 0.04 mmol) in DCM (0.4 mL) was added HATU (45 mg, 0.12mmol) and DIEA (10.3 mg, 0.08 mmol). After 30 min, dimethylamine (2Msolution in THF, 200 μL, 0.4 mmol) was added and the reaction stirredfor 18 h at room temperature. The reaction was quenched with water (100μL) and the solvent evaporated. The crude material was purified bypreparative HPLC to afford 14 mg (66%) of(R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide43 as white solid. LCMS-ESI (m/z) calculated for C₂₅H₂₇N₅O₄S₂: 525.2.found 526.2 [M+H]⁺, t_(R)=3.42 min. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (dd,J=8.9, 2.3 Hz, 1H), 8.14 (d, J=2.3 Hz, 1H), 7.82 (d, J=7.7 Hz, 1H), 7.73(d, J=7.6 Hz, 1H), 7.40 (t, J=7.7 Hz, 1H), 7.09 (d, J=9.0 Hz, 1H), 5.50(d, J=8.2 Hz, 1H), 5.07 (q, J=7.7 Hz, 1H), 4.76 (hept, J=6.1 Hz, 1H),4.28 (d, J=14.6 Hz, 1H), 4.09 (d, J=14.6 Hz, 1H), 3.50 (ddd, J=17.0,8.8, 3.4 Hz, 1H), 3.20 (dt, J=9.7, 7.1 Hz, 1H), 3.15 (s, 3H), 3.02 (s,3H), 2.72 (dtd, J=11.4, 8.0, 3.5 Hz, 1H), 2.20 (dq, J=13.1, 8.4 Hz, 1H),1.46 (d, J=6.1 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 166.99, 165.73,163.22, 161.71, 144.17, 141.92, 133.44, 133.34, 129.31, 127.92, 127.33,126.37, 122.70, 115.57, 113.91, 103.71, 72.56, 59.23, 54.92, 38.30,35.99, 31.36, 21.74. Chiral HPLC:(R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamidewas eluted in 40% IPA in hexanes, 100% ee, t_(R)=22.87 min.

(S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide 42 was prepared in an analogous fashionusing(S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl) acetic acid. Chiral HPLC: 97.8% ee, t_(R) forS-enantiomer=29.06 min.

(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-morpholino-2-oxoethanesulfonamide(Compound 162)

Prepared using General Procedure 16: To(R)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)aceticacid 158 (15 mg, 0.03 mmol) in DCM (0.4 mL) was added HATU (26 mg, 0.07mmol) and DIEA (7.8 mg, 0.06 mmol). After 30 min, morpholine (52 mg, 0.6mmol) was added and the reaction stirred for 18 h at room temperature.The reaction was quenched with water (100 μL) and the solventevaporated. The crude material was purified by preparative HPLC toafford 8 mg (47%) of(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-morpholino-2-oxoethanesulfonamide162. LCMS-ESI (m/z) calculated for C₂₈H₃₀N₄O₅S₂: 566.1. found 567.2[M+H]⁺, t_(R)=3.77 min.

General Procedure 17. Preparation of Indane Sulfonamide Alcohols

To a stirred solution of (R)- or (S)-indane sulfonamide ester (1 eq) inTHF (0.06 M) was added sodium borohydride (4 eq) at room temperature.The reaction was heated to 75° C. and methanol (10 eq) was addeddropwise. After 1 h, the reaction was cooled and concentrated. The pureproduct was obtained by preparative HPLC purification.

Compounds 45, 46, 164, and 165 were prepared using General Procedure 17.

(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide(Compound 46)

Prepared using General Procedure 17: To a stirred solution of (R)-methyl2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (13 mg, 0.02 mmol) in THF (0.5 mL) was added sodium borohydride(2.3 mg, 0.06 mmol) at room temperature. The reaction was heated to 75°C. and methanol (0.03 mL, 0.7 mmol) was added dropwise. After 1 h, thereaction was cooled and concentrated. Purification of the crude materialby preparative HPLC gave 6 mg (60%) of(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide46. LCMS-ESI (m/z) calculated for C₂₃H₂₄N₄O₄S₂: 484.1. found 485.1[M+H]⁺, t_(R)=3.26 min. ¹H NMR (400 MHz, CDCl₃) δ 8.23 (dd, J=8.9, 2.3Hz, 1H), 8.16 (d, J=2.3 Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.64 (d, J=7.6Hz, 1H), 7.43 (t, J=7.6 Hz, 1H), 7.11 (d, J=9.0 Hz, 1H), 5.19-4.96 (m,1H), 4.87-4.63 (m, 3H), 4.17 (dd, J=8.2, 4.4 Hz, 2H), 3.53 (ddd, J=17.2,8.8, 3.5 Hz, 1H), 3.46-3.34 (m, 2H), 3.32-3.11 (m, 1H), 2.86-2.59 (m,1H), 2.19-1.97 (m, 1H), 1.48 (d, J=6.1 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃)δ 166.83, 165.72, 161.71, 144.11, 141.85, 133.47, 133.26, 129.53,127.99, 126.92, 126.58, 122.64, 115.51, 113.87, 103.79, 72.54, 58.86,57.43, 55.67, 34.69, 31.27, 21.73. Chiral HPLC:(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamidewas eluted in MeOH, 96.2% ee, t_(R)=12.58 min (Chiral Method 2).

(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide45 was prepared in an analogous fashion using (S)-methyl2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate. Chiral HPLC: 97.6% ee, t_(R) for S-enantiomer=10.99min (Chiral Method 2).

(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide(Compound 165)

Prepared using General Procedure 17: To a stirred solution of (S)-methyl2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate(20 mg, 0.04 mmol) in THF (0.5 mL) was added sodium borohydride (3.6 mg,0.09 mmol) at room temperature. The reaction was heated to 75° C. andmethanol (0.06 mL, 1.4 mmol) was added dropwise. After 1 h, the reactionwas cooled and concentrated. Purification of the crude material bypreparative HPLC gave 12.2 mg (64%) of(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 165.LCMS-ESI (m/z) calculated for C₂₄H₂₅N₃O₄S₂: 483.1. found 484.2 [M+H]⁺,t_(R)=3.45 min.

(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide164 was prepared in an analogous fashion using (R)-methyl2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate.

General Procedure 18. Preparation of Indane Sulfamides

To a stirred solution of (R)- or (S)-indane amine (1 eq) in 1,4-dioxane(0.06M) was added sulfamide (5 eq) and the reaction was stirred at 90°C. for 16 h. The solvent was evaporated and the reaction mixture waspurified by preparative HPLC.

Compounds 47, 48, 166, and 167 were prepared using General Procedure 18.

(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide(Compound 47)

Prepared using General Procedure 18: To(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 4 (25 mg, 0.06 mmol) in dioxane (1 mL) was added sulfamide(30 mg, 0.3 mmol) and the mixture was heated to 90° C. After 16 h, thesolvent was evaporated and the residue was purified by columnchromatography. Additional purification by recrystallization from MeOHprovided 15.9 mg (26%) of(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 47. LCMS-ESI (m/z) calculated for C₂₁H₂₁N₅O₃S₂: 455.1. found456.1 [M+H]⁺, t_(R)=3.33 min. ¹H NMR (400 MHz, DMSO) δ 8.40 (d, J=2.3Hz, 1H), 8.32 (dd, J=8.9, 2.4 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.66 (d,J=7.6 Hz, 1H), 7.56-7.38 (m, 2H), 7.23 (d, J=9.0 Hz, 1H), 6.75 (s, 2H),4.95 (dt, J=12.2, 6.1 Hz, 1H), 4.87 (dd, J=16.6, 8.2 Hz, 1H), 3.42-3.26(m, 1H), 3.07 (dt, J=16.4, 8.3 Hz, 1H), 2.61 (dtd, J=11.0, 7.9, 3.0 Hz,1H), 2.00 (dq, J=12.7, 8.8 Hz, 1H), 1.38 (d, J=6.0 Hz, 6H). ¹³C NMR (101MHz, DMSO) δ 166.64, 165.62, 161.19, 146.08, 141.36, 133.89, 133.15,127.97, 127.51, 127.27, 125.78, 122.22, 115.57, 114.95, 102.29, 72.17,57.67, 33.41, 30.73, 21.52. Chiral HPLC:(S)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide was eluted in MeOH: 98.6% ee, t_(R)=7.63 min (Chiral Method2).

(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 48 was prepared in an analogous fashion using(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride. Chiral HPLC: 98% ee, t_(R) for R-enantiomer=9.10 min(Chiral Method 2).

(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide(Compound 166)

Prepared using General Procedure 18: To(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 72 (100 mg, 0.02 mmol) in dioxane (1 mL) was added DIEA(58 mg, 0.32 mmol) and sulfamide (115 mg, 1.2 mmol) and the reaction washeated to 90° C. for 4 h. The solvent was evaporated and the residue wasdiluted with EA (10 mL) and washed with successively with NH₄Cl andbrine. The product was purified by column chromatography (MeOH/DCM) toyield 80 mg (73%) of(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide166. LCMS-ESI (m/z) calculated for C₂₂H₂₂N₄O₃S₂: 454.1. found 455.4[M+H]⁺, t_(R)=3.46 min. ¹H NMR (400 MHz, DMSO) δ 8.29 (d, J=2.3 Hz, 1H),8.23 (dd, J=8.9, 2.4 Hz, 1H), 8.16 (s, 1H), 7.55 (d, J=7.6 Hz, 1H), 7.47(dd, J=18.4, 8.3 Hz, 2H), 7.36 (t, J=7.6 Hz, 1H), 7.17 (d, J=9.0 Hz,1H), 6.73 (s, 2H), 4.98-4.75 (m, 2H), 3.19-3.05 (m, 1H), 3.00 (dd,J=16.3, 8.0 Hz, 1H), 2.61-2.54 (m, 1H), 2.04-1.89 (m, 1H), 1.38 (t,J=5.5 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 165.43, 161.42, 144.43,141.31, 140.70, 138.02, 132.43, 132.20, 128.52, 128.18, 128.08, 126.65,124.98, 116.30, 114.25, 103.78, 72.82, 59.25, 34.62, 31.13, 22.14.Chiral HPLC:(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamidewas eluted in 50% ethanol in hexanes, 99.0% ee, t_(R)=40.47 min.

(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 167 was prepared in an analogous fashion using(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile71. Chiral HPLC: 99.1% ee, t_(R) for S-enantiomer=27.67 min.

General Procedure 19. Preparation of Indane Ureas

To a stirred solution of CDI (1.7 eq) in DCM (0.16M) was added thestirred suspension of (R)- or (S)-indane amine (1 eq) and Et₃N (3 eq) inDCM (0.16M) and the mixture was stirred for 2 h or until all the indaneamine consumed. If necessary, additional CDI was added. This solutionwas added to the appropriate amine and the reaction mixture stirred atroom temperature for 16 h. The solvent was evaporated and the pureproduct isolated after preparative HPLC.

Compounds 50-67 and 168-205 were prepared using General Procedure 19.

(R)—N—((R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide(Compound 56)

Prepared using General Procedure 19: To a CDI ((13.4 mg, 0.08 mmol) inDCM (0.5 mL) was added a suspension of(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 5 (20.0 mg, 0.04 mmol) and Et₃N (14.7 mg, 0.14 mmol) inDCM (0.5 mL) and the mixture stirred for 2 h at room temperature. Theresulting solution was added to the preparative solution ofazetidin-3-ol hydrochloride (15.9 mg, 0.14 mmol)) at room temperature.The reaction was stirred at room temperature for 16 h. The solvent wasevaporated and the crude material was purified by preparative HPLC toafford 15 mg of (62%) of(R)—N—((R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide56. LCMS-ESI (m/z) calculated for C₂₈H₃₂N₆O₂S: 516.2. found 517.2[M+H]⁺, t_(R)=2.43 min. ¹H NMR (400 MHz, DMSO) δ 8.40 (d, J=2.4 Hz, 1H),8.32 (dd, J=9.0, 2.4 Hz, 1H), 7.99-7.76 (m, 1H), 7.51 (d, J=9.2 Hz, 1H),7.49-7.34 (m, 2H), 6.73 (d, J=8.4 Hz, 1H), 5.32 (d, J=8.2 Hz, 1H),5.09-4.80 (m, 1H), 3.86 (dd, J=14.3, 7.0 Hz, 1H), 3.75 (dd, J=11.0, 7.5Hz, 1H), 3.63-3.48 (m, 1H), 3.45-3.22 (m, 3H), 3.10 (dt, J=16.5, 8.3 Hz,1H), 2.82 (t, J=5.1 Hz, 6H), 2.56-2.40 (m, 1H), 2.32 (dd, J=9.8, 2.5 Hz,1H), 2.15-2.02 (m, 1H), 2.00-1.81 (m, 1H), 1.38 (d, J=6.0 Hz, 6H). ¹³CNMR (101 MHz, CDCl₃) δ 167.10, 165.84, 161.80, 145.94, 142.30, 133.54,133.36, 128.86, 127.82, 126.94, 126.41, 122.72, 115.78, 114.01, 103.72,72.71, 64.71, 55.95, 46.76, 44.20, 42.04, 34.06, 31.45, 27.30, 21.90,21.89.

(S)—N—((R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide57 was prepared in an analogous fashion using(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride.

(R)—N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)morpholine-4-carboxamide(compound 58)

Prepared using General Procedure 19. LCMS-ESI (m/z) calculated forC₂₆H₂₇N₅O₃S: 489.2. found 490.2 [M+H]⁺, t_(R)=3.54 min. ¹H NMR (400 MHz,CDCl₃) δ 8.20 (dd, J=8.9, 2.3 Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.82 (d,J=7.7 Hz, 1H), 7.49 (d, J=7.5 Hz, 1H), 7.36 (t, J=7.6 Hz, 1H), 7.08 (d,J=9.0 Hz, 1H), 5.51 (d, J=7.6 Hz, 1H), 4.83-4.56 (m, 2H), 3.71 (dd,J=10.0, 5.0 Hz, 4H), 3.54-3.33 (m, 5H), 3.29-3.05 (m, 1H), 2.81-2.56 (m,1H), 1.91 (ddd, J=16.4, 13.1, 7.9 Hz, 1H), 1.46 (d, J=6.1 Hz, 6H). ¹³CNMR (101 MHz, CDCl₃) δ 167.45, 166.17, 162.16, 157.98, 146.58, 142.87,133.90, 133.77, 129.34, 128.20, 127.29, 126.95, 123.21, 116.06, 114.36,104.22, 73.03, 66.92, 56.41, 44.54, 34.72, 31.85, 22.25.

(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-1-carboxamide(Compound 172)

Prepared using General Procedure 19: To CDI (117 mg, 0.72 mmol) in DCM(1 mL) was added a suspension of(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 72 (150 mg, 0.36 mmol), Et₃N (145 mg, 1.44 mmol) and DCM(1 mL) and the mixture stirred for 2 h at room temperature. Theresulting solution was added to the preparative solution of pyrrolidine(77 mg, 1.08 mmol)) at room temperature. The reaction was stirred atroom temperature for 16 h. The solvent was evaporated and the crudematerial was purified by preparative HPLC to afford 110 mg of (78%) of(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-1-carboxamide172. LCMS-ESI (m/z) calculated for C₂₇H₂₈N₄O₂S: 472.1. found 473.2[M+H]⁺, t_(R)=3.79 min. ¹H NMR (400 MHz, DMSO) δ 8.28 (d, J=2.3 Hz, 1H),8.22 (dd, J=8.9, 2.4 Hz, 1H), 8.15 (s, 1H), 7.53 (d, J=7.3 Hz, 1H), 7.44(d, J=9.1 Hz, 1H), 7.36-7.24 (m, 2H), 6.42 (d, J=8.6 Hz, 1H), 5.29 (q,J=8.4 Hz, 1H), 4.91 (hept, J=5.9 Hz, 1H), 3.31-3.20 (m, 4H), 3.17-2.95(m, 2H), 2.43 (ddd, J=10.7, 6.2, 2.8 Hz, 1H), 2.00-1.87 (m, 1H),1.87-1.72 (m, 4H), 1.37 (d, J=6.0 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ164.79, 160.90, 156.46, 146.16, 141.10, 140.75, 137.75, 131.89, 131.80,127.75, 127.71, 127.63, 126.53, 124.27, 115.92, 113.78, 103.60, 72.34,55.78, 45.61, 34.87, 30.80, 25.57, 21.81.

(S)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-1-carboxamide173 was prepared in an analogous fashion using(S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrilehydrochloride 71.

(R)—N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)morpholine-4-carboxamide(Compound 186)

Prepared using General Procedure 19. LCMS-ESI (m/z) calculated forC₂₇H₂₈N₄O₃S: 488.2. found 489.2 [M+H]⁺, t_(R)=3.54 min. ¹H NMR (400 MHz,DMSO) δ 8.28 (d, J=2.3 Hz, 1H), 8.22 (dd, J=8.9, 2.4 Hz, 1H), 8.16 (s,1H), 7.54 (d, J=7.5 Hz, 1H), 7.44 (d, J=9.1 Hz, 1H), 7.36-7.24 (m, 2H),6.89 (d, J=8.3 Hz, 1H), 5.30 (d, J=8.2 Hz, 1H), 4.99-4.83 (m, 1H),3.61-3.50 (m, 4H), 3.42-3.24 (m, 4H), 3.23-2.91 (m, 2H), 2.48-2.40 (m,1H), 2.00-1.82 (m, 1H), 1.37 (d, J=6.0 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃)δ 165.23, 161.35, 157.93, 146.06, 141.53, 141.16, 138.11, 132.35,132.20, 128.26, 128.14, 126.90, 124.68, 116.38, 114.20, 103.97, 72.80,66.91, 56.53, 44.50, 34.89, 31.31, 22.26.

General Procedure 20. Preparation of Indane Amines from Indanols

To a flask containing the indanol (1 eq) in DCM (0.14M) at 0° C. wasadded SOCl₂ (2 eq). After stirring for 30 min, the reaction mixture wasconcentrated in vacuo and placed under high vacuum for 2 h. Theresulting crude chloride was dissolved in DMA (0.02M). The amine (3 eq),DIEA (3 eq), and in some cases NaBr (3 eq) were added and the resultingreactions were stirred at 55-60° C. overnight and purified either bypreparative HPLC or column chromatography.

Compounds 206-219 and were prepared using General Procedure 20.

5-(5-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile(Compound 207)

Prepared using General Procedure 20: To a stirred solution of5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile(20 mg, 0.05 mmol) in DCM (1 mL) was added thionyl chloride (12.6 mg,0.106 mmol) at 0° C. The reaction was stirred at room temperature for 3h. The solvent was evaporated and the crude chloride re-dissolved indimethyl acetamide (1 mL). Diisopropyl ethylamine (20.5 mg, 0.16 mmol)and ethanolamine (9.7 mg, 0.16 mmol) were added and the reaction mixturewas stirred at 70° C. overnight. The reaction mixture was quenched withwater (200 uL) and purified by preparative HPLC to afford 11 mg (46%) of5-(5-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile208. LCMS-ESI (m/z) calculated for C₂₅H₂₅N₃O₂S: 431.1. found 432.1[M+H]⁺, t_(R)=6.48 min (Method 2).

2-fluoro-5-(thiazol-5-yl)benzonitrile (THZ INT-3)

To 5-(tributylstannyl)thiazole (1.00 g, 2.7 mmol) in THF (10 mL) wasadded 2-fluoro-5-iodobenzonitrile (0.791 g, 3.2 mmol). The solution wasdegassed with N₂ and bis(triphenylphosphine)palladium(II) chloridePd(Ph)₂Cl₂ (0.187 g, 0.27 mmol) was added. The solution was furtherdegassed for five minutes before heating to 85° C. for 2 h. Uponcooling, the reaction mixture was diluted with saturated NaHCO₃ andwashed with EA (3×50 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated. The crude product was purified bychromatography (10% EA/Hexanes) to afford 0.450 g (82%) of2-fluoro-5-(thiazol-5-yl)benzonitrile THZ INT-3 as a tan solid. LCMS-ESI(m/z) calculated for C₁₀H₅FN₂S: 204.2. found 205.0 [M+H]⁺, t_(R)=3.00min.

5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile (THZ INT-4)

To a stirring solution of 2-fluoro-5-(thiazol-5-yl)benzonitrile THZINT-3 (0.429 g, 2.1 mmol) in acetic acid (10.5 mL) was added potassiumacetate (0.412 g, 4.2 mmol). Bromine (0.647 mL, 12.6 mmol) was addeddropwise over 10 minutes and the reaction mixture stirred at roomtemperature for 48 h. The reaction mixture was basified with 1N NaOH andwashed with EA and brine. The combined organic layers were dried overMgSO₄, filtered, and concentrated. The crude product was purified bychromatography (20% EA/Hexanes) to produce 0.10 g (30%) of5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile THZ INT-4. LCMS-ESI (m/z)calculated for C₁₀H₄BrFN₂S: 283.1. found 284.9 [M+H]⁺, t_(R)=3.33 min.

5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-fluorobenzonitrile

Prepared using General Procedure 1. To5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile THZ INT-4 (0.100 g, 0.35mmol),tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)silane IND INT-8 (0.143 g, 0.38 mmol) and sodium carbonate (0.112 g, 1.1mmol) in dioxane (1.8 mL) and H₂O (0.2 mL) was addedtetrakis(triphenylphosphine)palladium (0.041 g, 0.035 mmol). Thesolution was degassed with N₂ and the reaction mixture heated at 85° C.for 6 h. Upon cooling, the reaction mixture was diluted with brine andwashed with DCM (3×100 mL). The combined organic layers were dried overMgSO₄, filtered, and concentrated. The crude product was purified bychromatography (30% EA/Hexanes) to produce 0.05 g (32%) of5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-fluorobenzo-nitrileas a white solid. LCMS-ESI (m/z) calculated for C₂₅H₂₇FN₂OSSi: 450.6.found 451.1 [M+H]⁺, t_(R)=4.84 min (Method 3).

5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-M-inden-4-yl)thiazol-5-yl)-2-isopropoxy-benzonitrile

Prepared using General Procedure 2. To a solution of5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-fluorobenzonitrile(0.043 g, 0.095 mmol) in isopropanol (2 mL) was added sodiumisopropoxide (0.07 g, 0.090 mmol). The reaction mixture was heated at60° C. for 12 h. Upon cooling, the solvent was removed under a stream ofN₂ and the crude reaction mixture was carried onto the next step withoutfurther purification. LCMS-ESI (m/z) calculated for C₂₈H₃₄N₂O₂SSi:490.7, t_(R)=5.06 min (Method 3).

5-(2-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxy-benzonitrile(Compound 222)

Prepared using General Procedure 3. To crude5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile(0.043 g, 0.095 mmol) was added 4N HCl in dioxane (1.0 mL). The reactionmixture was stirred at room temperature for 2 h. The solvent wasconcentrated under a stream of N₂ and the mixture dissolved in MeOH (1.0mL). The crude product was purified by preparative HPLC to yield 0.02 g(43%) of5-(2-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile222. LCMS-ESI (m/z): calcd for: C₂₂H₂₀N₂O₂S: 376.5. found 377.1 [M+H]⁺,t_(R)=3.31 min.

2-isopropoxy-5-(thiophen-2-yl)benzonitrile (THIO INT-1)

A microwave vial was charged with 5-bromo-2-isopropoxybenzonitrile (200mg, 0.83 mmol), thiophen-2-ylboronic acid (106.5 mg, 0.83 mmol),potassium carbonate (345.3 mg, 2.49 mmol) and 3:1 mixture ofdimethylethylene glycol/H₂O (2 mL). The reaction mixture was degassed bybubbling N₂ gas through the stirred solution for 10 min. Pd(PPh₃)₄ (20.4mg, 0.02 mmol) was added and the solution degassed for additional 2 min.The vial was subjected to microwave irradiation at 100° C. for 30 min.The solvent was removed and the residue dissolved in EA (10 mL), washedwith brine, and dried over MgSO₄. The product was purifiedchromatography (EA/hexanes) to afford 165 mg (82%) of2-isopropoxy-5-(thiophen-2-yl)benzonitrile THIO INT-1 as colorless oil.LCMS-ESI (m/z) calculated for C₁₄H₁₃NOS: 243.1. found 266.0 [M+Na]⁺,t_(R)=3.90 min. ¹H NMR (400 MHz, CDCl₃) δ 7.74 (d, J=2.3 Hz, 1H), 7.69(dd, J=8.8, 2.4 Hz, 1H), 7.28-7.23 (m, 1H), 7.19 (dd, J=3.6, 1.1 Hz,1H), 7.05 (dd, J=5.1, 3.6 Hz, 1H), 6.95 (d, J=8.8 Hz, 1H), 4.65 (dt,J=12.2, 6.1 Hz, 1H), 1.43-1.37 (m, 6H).

5-(5-bromothiophen-2-yl)-2-isopropoxybenzonitrile (THIO INT-2)

To a solution of 2-isopropoxy-5-(thiophen-2-yl)benzonitrile THIO INT-1(160 mg, 0.66 mmol) in anhydrous DMF (5 mL) was added freshlycrystallized N-bromosuccinimide (118 mg, 0.66 mmol) at 0° C. Thereaction mixture was stirred at room temperature for 3 h (longerreaction times and use of excess NBS caused dibromination). The reactionmixture was diluted with EA (10 mL), washed with water (2×10 mL) andbrine, and dried over MgSO₄. The crude product was purified by silicagel column (EA/hexanes) to provide 126 mg (60%) of5-(5-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-2 as whitesolid. LCMS-ESI (m/z) calculated for C₁₄H₁₂BrNOS: 320.9; no M+,t_(R)=4.26 min. ¹H NMR (400 MHz, CDCl₃) δ 7.60 (d, J=2.3 Hz, 1H), 7.53(dd, J=8.8, 2.4 Hz, 1H), 6.95 (d, J=3.9 Hz, 1H), 6.89 (t, J=6.2 Hz, 2H),4.60 (dt, J=12.1, 6.1 Hz, 1H), 1.35 (d, J=6.1 Hz, 6H).

5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-M-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile

Prepared from 5-(5-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIOINT-2 and(±)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilaneIND INT 8 using General Procedure 1. LCMS-ESI (m/z) calculated forC₂₉H₃₅NO₂SSi: 489.2; no M+ found, t_(R)=8.10 min (Method 1). ¹H NMR (400MHz, CDCl₃) δ 7.77 (d, J=2.3 Hz, 1H), 7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.44(t, J=4.4 Hz, 1H), 7.27 (d, J=4.5 Hz, 2H), 7.17 (dd, J=12.5, 3.8 Hz,2H), 6.96 (d, J=8.9 Hz, 1H), 5.29 (t, J=7.1 Hz, 1H), 4.78-4.55 (m, 1H),3.21 (ddd, J=15.9, 8.8, 2.8 Hz, 1H), 2.95 (dt, J=16.2, 8.1 Hz, 1H),2.56-2.36 (m, 1H), 1.94 (dd, J=12.6, 7.3 Hz, 1H), 1.41 (d, J=6.1 Hz,6H), 1.01-0.86 (m, 9H), 0.17 (d, J=9.3 Hz, 6H).

5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile(Compound 223)

To a stirred solution of5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile(80 mg, 0.16 mmol) in 1,4-dioxane (1 mL) was added 4N HCl solution in1,4-dioxane (1 mL). The reaction mixture was stirred at room temperaturefor 2 h. Solvent was evaporated and the crude product was purified bychromatography (EA/hexanes) to afford 26 mg (40%) of5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile223 as a white solid. LCMS-ESI (m/z) calculated for C₂₃H₂₁NO₂S: 375.1.found 398.1 [M+Na]⁺, t_(R)=3.96 min. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (d,J=2.3 Hz, 1H), 7.71 (dd, J=8.8, 2.4 Hz, 1H), 7.53-7.45 (m, 1H), 7.38 (d,J=7.4 Hz, 1H), 7.30 (t, J=7.5 Hz, 1H), 7.19 (q, J=3.8 Hz, 2H), 6.97 (d,J=8.9 Hz, 1H), 5.28 (t, J=6.1 Hz, 1H), 4.66 (dt, J=12.2, 6.1 Hz, 1H),3.28 (ddd, J=16.2, 8.5, 4.7 Hz, 1H), 3.11-2.91 (m, 1H), 2.53 (dddd,J=13.1, 8.2, 6.9, 4.7 Hz, 1H), 2.08-1.92 (m, 1H), 1.57 (s, 1H), 1.41 (d,J=6.1 Hz, 6H). ¹³C NMR (101 MHz, CDCl₃) δ 159.37, 146.65, 142.74,141.52, 140.36, 131.55, 131.08, 130.96, 130.79, 127.79, 127.54, 126.67,123.82, 116.57, 114.40, 103.82, 76.59, 72.43, 36.07, 30.88, 22.08.

5-(5-(1-(2-hydroxyethylamino)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile(Compound 224)

Prepared using General Procedure 20 from5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrileand ethanolamine. LCMS-ESI (m/z) calculated for C₂₅H₂₆N₂O₂S: 418.2.found 419.1 [M+H]⁺, t_(R)=2.73 min.

(R)-tert-butyl4-(5-(3-cyano-4-isopropoxyphenyl)thiophen-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate

A 20 mL microwave vial was charged with (R)-tert-butyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamateIND INT-18 (44 mg, 0.12 mmol),5-(5-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-2 (40 mg,0.12 mmol), potassium carbonate (51 mg, 0.37 mmol) and a 3:1 mixture ofdimethylethylene glycol/H₂O (2 mL). The reaction mixture was degassed bybubbling N₂ gas through the stirred solution for 10 min. Pd(PPh₃)₄ (10.1mg, 0.008 mmol) was added and the solution degassed for an additional 2min. The vial was subjected to microwave irradiation at 100° C. for 30min. The solvent was removed and the residue dissolved in EA (10 mL),washed with brine, and dried over MgSO₄. The product was purified bychromatography (EA/hexanes) to afford 15 mg (51%) of (R)-tert-butyl4-(5-(3-cyano-4-isopropoxyphenyl)thiophen-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamateas an off-white solid. LCMS-ESI (m/z) calculated for C₂₈H₃₀N₂O₃S: 474.2;no M+ found, t_(R)=4.43 min. ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=2.3Hz, 1H), 7.70 (dd, J=8.8, 2.4 Hz, 1H), 7.45 (dd, J=6.3, 2.2 Hz, 1H),7.27 (d, J=6.6 Hz, 2H), 7.17 (dd, J=11.9, 3.8 Hz, 2H), 6.97 (d, J=8.9Hz, 1H), 5.30-5.11 (m, 1H), 4.78 (d, J=8.6 Hz, 1H), 4.66 (dt, J=12.2,6.1 Hz, 1H), 3.18 (ddd, J=16.1, 8.7, 3.4 Hz, 1H), 3.02 (dt, J=16.1, 8.1Hz, 1H), 2.68-2.51 (m, 1H), 1.90-1.73 (m, 1H), 1.47 (d, J=8.2 Hz, 9H),1.41 (d, J=6.1 Hz, 6H).

(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile(Compound 225)

Prepared using General Procedure 5. To a stirred solution of(R)-tert-butyl4-(5-(3-cyano-4-isopropoxyphenyl)thiophen-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate(15 mg, 0.03 mmol) in 1,4-dioxane (1 mL) was added 4N HCl solution in1,4-dioxane (0.5 mL). The reaction mixture was stirred at roomtemperature for 16 h. Solvent was evaporated the resulting solid wasdissolved 1:1 DMSO:MeOH (1 mL) and purified by preparative HPLC toafford 10 mg (90%) of(R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile225 as a white solid. LCMS-ESI (m/z) calculated for C₂₃H₂₂N₂OS: 374.2.found 358.1. [M-NH₂]⁺, t_(R)=2.69 min.

5-(4-bromothiophen-2-yl)-2-isopropoxybenzonitrile (THIO INT-3)

A 2 mL microwave vial was charged with 2,4-dibromothiophene (20 mg, 0.08mmol), (3-cyano-4-isopropoxyphenyl)boronic acid (17 mg, 0.08 mmol),potassium carbonate (35 mg, 0.25 mmol) and 3:1 mixture of DME/H₂O (4mL). The reaction mixture was degassed by bubbling N₂ through thestirred solution for 10 min. Pd(PPh₃)₄ (7 mg, 0.006 mmol) was added andthe solution degassed for an additional 2 min. The vial was subjected tomicrowave irradiation at 70° C. for 30 min or until starting materialconsumed. 5-(4-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-3was used in the next experiment without purification. LCMS-ESI (m/z)calculated for C₁₄H₁₂BrNOS: 320.9; no M+ observed, t_(R)=4.15 min.

5-(4-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile

Prepared from 5-(4-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIOINT-3 (0.08 mmol) andtert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silaneIND INT-8 (31 mg, 0.08 mmol) using General Procedure 1, to afford 12 mg(30%, for two steps) of5-(4-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile.LCMS-ESI (m/z) calculated for C₂₉H₃₅NO₂SSi: 489.2; no M+ found,t_(R)=6.66 min (Method 1). ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=2.3 Hz,1H), 7.70 (dd, J=8.8, 2.4 Hz, 1H), 7.36-7.31 (m, 2H), 7.29-7.25 (m, 2H),7.25-7.19 (m, 1H), 6.96 (d, J=8.9 Hz, 1H), 5.28 (t, J=6.9 Hz, 1H),4.73-4.50 (m, 1H), 3.09 (ddd, J=15.8, 8.7, 2.9 Hz, 1H), 2.88 (dt,J=16.0, 8.1 Hz, 1H), 2.47-2.30 (m, 1H), 1.96-1.81 (m, 1H), 1.40 (d,J=6.1 Hz, 6H), 0.94 (s, 9H), 0.16 (d, J=9.9 Hz, 6H).

5-(4-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile(Compound 226)

Prepared using General Procedure 3. To a solution of5-(4-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile(17 mg, 0.03 mmol) in THF (1 mL) was added 1M solution of TBAF intetrahydrofuran (0.3 mL, 0.3 mmol) and the reaction mixture was stirredat room temperature overnight. The reaction mixture was concentrated andpurified by preparative HPLC to yield 8 mg (46%) of5-(4-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile226 as white solid. LCMS-ESI (m/z) calculated for C₂₃H₂₁NO₂S: 375.1.found 398.1 [M+Na]⁺. t_(R)=3.84 min; ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d,J=2.3 Hz, 1H), 7.72 (dd, J=8.8, 2.4 Hz, 1H), 7.43-7.36 (m, 2H),7.35-7.28 (m, 1H), 7.26 (d, J=1.4 Hz, 1H), 7.24 (s, 1H), 7.06-6.89 (m,1H), 5.29 (t, J=6.1 Hz, 1H), 4.77-4.49 (m, 1H), 3.20 (ddd, J=16.0, 8.4,4.7 Hz, 1H), 3.01-2.86 (m, 1H), 2.50 (dddd, J=13.0, 8.1, 6.8, 4.7 Hz,1H), 2.11-1.88 (m, 1H), 1.58 (s, 1H), 1.41 (d, J=6.1 Hz, 6H); ¹³C NMR(101 MHz, CDCl₃) δ 159.51, 146.35, 142.55, 142.00, 140.88, 133.16,131.79, 131.24, 128.14, 127.69, 127.56, 124.16, 123.54, 122.06, 116.54,114.39, 103.84, 76.68, 72.45, 36.28, 30.50, 22.08.

(4-(4-bromothiophen-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane(THIO INT-4

Prepared using General Procedure 1. A 2 mL microwave vial was chargedwith 2,4-dibromothiophene (15 mg, 0.06 mmol),tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silaneIND INT-8 (23 mg, 0.06 mmol), potassium carbonate (26 mg, 0.18 mmol) and3:1 mixture of DME/H₂O (2 mL). The reaction mixture was degassed bybubbling N₂ through the stirred solution for 10 min. Pd(PPh₃)₄ (5 mg,0.004 mmol) was added and the solution degassed for an additional 2 min.The vial was subjected to microwave irradiation at 70° C. for 30 min oruntil starting material consumed. The resulting((4-(4-bromothiophen-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilaneTHIO INT-4 was carried onto the next experiment without workup andpurification. LCMS-ESI (m/z) calculated for C₁₉H₂₅BrOSSi: 408.1; no M+found, t_(R)=6.50 min (Method 1).

2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile

A suspension of 5-bromo-2-isopropoxybenzonitrile (200 mg, 0.83 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (233.7 mg,920 mmol), and potassium acetate (246 mg, 2.5 mmol) in anhydrous1,4-dioxane (100 mL) was degassed by passing N₂ through the solution for30 min. PdCl₂(dppf).CH₂Cl₂ (136 mg, 0.16 mmol) was added and thereaction mixture was heated at 85° C. for 6 h. The solvent was removedunder vacuum and the residue was dissolved in EA (100 mL) and filteredthrough celite. The filtrate was washed with water and brine, dried overMgSO₄, and purified by chromatography (EA/hexanes) to afford 40 mg (13%)of2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileas white solid. LCMS-ESI (m/z) calculated for C₁₆H₂₂BNO₃: 287.2. found288.2 [M+H]⁺, t_(R)=4.07 min. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=1.5Hz, 1H), 7.88 (dd, J=8.5, 1.7 Hz, 1H), 6.91 (d, J=8.5 Hz, 1H), 4.67 (dt,J=12.2, 6.1 Hz, 1H), 1.38 (d, J=6.1 Hz, 6H), 1.30 (s, 12H).

5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-M-inden-4-yl)thiophen-3-yl)-2-isopropoxybenzonitrile(THIO INT-5)

To the crude reaction mixture containing((4-(4-bromothiophen-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilaneTHIO INT-4 (0.12 mmol) in 3:1 mixture of DME/H₂O (4 mL) was added2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile(17.9 mg, 0.06 mmol) and the solution was degassed for 2 min. Pd(PPh₃)₄(7 mg, 0.006 mmol) was added and the reaction mixture degassed for anadditional 2 min. The reaction mixture was heated under microwavecondition at 100° C. for 30 min. The reaction mixture was diluted withEA (10 mL), washed with water and brine, and dried over MgSO₄. The crudeproduct was purified by silica gel column chromatography (EA/Hexanes) toafford 12 mg (40%, for two steps) of5-(4-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrileTHIO INT-5. LCMS-ESI (m/z) calculated for C₂₉H₃₅NO₂SSi: 489.2; no M+found, t_(R)=6.66 min (Method 1).

5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-3-yl)-2-isopropoxybenzonitrile(Compound 227)

Prepared using General Procedure 3. To a solution of5-(4-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrileTHIO INT-5 (12 mg, 0.02 mmol) in THF (1 mL) was added 1M solution ofTBAF in tetrahydrofuran (0.2 mL, 0.2 mmol) and the reaction mixture wasstirred at room temperature overnight. The reaction mixture wasconcentrated and purified by preparative HPLC to yield 3 mg (22%) of5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-3-yl)-2-isopropoxybenzonitrile227 as white solid. LCMS-ESI (m/z) calculated for C₂₃H₂₁NO₂S: 375.1.found 398.1 [M+Na]⁺. t_(R)=3.85 min; ¹H NMR (400 MHz, CDCl₃) δ 7.77 (dd,J=6.9, 2.2 Hz, 1H), 7.74-7.68 (m, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.45-7.36(m, 1H), 7.36-7.28 (m, 1H), 7.27-7.22 (m, 2H), 7.10-6.74 (m, 1H),5.37-5.15 (m, 1H), 4.67 (dt, J=12.2, 6.1 Hz, 1H), 3.90 (ddd, J=16.2,8.5, 4.7 Hz, 1H), 3.14-2.98 (m, 1H), 2.66-2.40 (m, 1H), 2.09-1.87 (m,1H), 1.57 (s, 1H), 1.41 (d, J=6.1 Hz, 6H).

Selected compounds and their corresponding analytical data is shown inTable 1, where the LCMS data was collected using Method 2 (see GeneralMethods). The enantiomeric purity was determined for key intermediatesand selected final compounds and is presumed from the synthesis for theremaining compounds.

TABLE 1 LCMS COMPOUND RETENTION STRUCTURE NUMBER TIME (min)

1 8.53

2 8.54

3 8.52

4 6.08

5 6.08

6 5.98

7 7.82

8 7.78

9 6.18

10 6.18

11 8.68

12 8.70

13 6.43

14 8.26

15 8.26

16 9.26

17 6.19

18 6.09

19 6.42

20 6.48

21 6.34

22 6.30

23 6.50

24 6.35

25 6.31

26 6.44

27 6.41

28 6.21

29 6.10

30 6.81

31 6.38

32 6.32

33 8.84

34 8.80

35 9.10

36 9.13

37 6.52

38 6.54

39 6.46

40 8.37

41 8.33

42 8.58

43 8.55

44 7.95

45 8.21

46 8.18

47 8.29

48 8.26

49 6.23

50 7.75

51 7.81

52 8.88

53 8.92

54 7.61

55 7.65

56 6.26

57 6.30

58 8.39

59 8.43

60 8.02

61 7.98

62 7.75

63 7.79

64 7.60

65 7.55

66 8.55

67 8.58

68 9.25

69 9.11

70 9.12

71 6.20

72 6.29

73 8.22

74 8.22

75 9.23

76 9.22

77 6.47

78 6.45

79 6.42

80 6.44

81 6.62

82 6.63

83 9.99

84 9.98

85 6.93

86 6.92

87 8.74

88 8.75

89 9.77

90 9.76

91 6.39

92 6.34

93 6.80

94 6.62

95 6.47

96 6.65

97 6.63

98 6.54

99 6.57

100 6.83

101 6.66

102 6.34

103 6.36

104 6.28

105 6.31

106 6.43

107 6.78

108 5.40

109 6.43

110 6.51

111 9.24

112 9.25

113 9.54

114 9.56

115 9.44

116 9.55

117 9.72

118 9.70

119 10.32

120 10.33

121 7.15

122 6.99

123 6.99

124 6.81

125 6.72

126 6.89

127 7.04

128 6.90

129 6.95

130 7.15

131 6.73

132 6.72

133 6.90

134 6.88

135 6.27

136 6.24

137 6.78

138 6.78

139 7.09

140 7.25

141 6.81

142 6.84

143 6.93

144 6.95

145 6.72

146 6.84

147 7.38

148 7.02

149 6.90

150 6.88

151 6.83

152 6.75

153 6.52

154 9.50

155 9.48

156 9.54

157 9.50

158 8.73

159 8.69

160 8.71

161 8.74

162 8.89

163 8.39

164 8.66

165 8.66

166 8.66

167 8.65

168 9.05

169 9.06

170 7.95

171 7.93

172 9.40

173 9.41

174 8.01

175 7.99

176 8.02

177 8.02

178 6.53

179 6.54

180 6.42

181 6.45

182 6.51

183 6.62

184 6.55

185 6.57

186 8.87

187 8.87

188 6.42

189 6.39

190 6.60

191 6.57

192 6.65

193 6.66

194 8.41

195 8.41

196 8.39

197 8.42

198 8.45

199 8.43

200 8.59

201 8.61

202 8.17

203 8.15

204 9.61

205 9.62

206 6.80

207 6.47

208 6.93

209 6.53

210 6.57

211 5.76

212 5.82

213 6.96

214 6.62

215 7.45

216 6.78

217 6.65

218 7.45

219 6.67

220 6.65

221 6.58

222 8.16

223 9.88

224 6.88

225 6.83

226 9.68

227 9.68

Biological Assays Assay Procedures

Generation of S1P₁-Mediated Inhibition of cAMP Reporter Assay

A mammalian expression plasmid containing S1P₁/EDG1 cloned into pcDNA3.1was purchased from Missouri S&T cDNA Resource Centre. The nucleotide andamino acid sequence of human S1P₁/EDG1 are published in Hla and Maciag(J Biol Chem, 265(1990), 9308-9313). S1P₁/pcDNA3.1 was transfected intothe CRE-bla CHO K1 (Invitrogen) cell line, and stable single cell cloneswere selected using standard techniques. Expression of functionalS1P₁/EDG1 receptor was confirmed by cell surface FACS with a S1P₁antibody (R&D Systems, clone 218713) and S1P-mediated inhibition ofForskolin induced cAMP.

S1P₁ CRE-bla CHOK1 reporter assay—characterization of S1P₁ agonists

Cells were seeded into 384-well black wall/clear bottom plates at 10⁴cells/well/19.5 μl assay media (DMEM-phenol free, 0.5% charcoal/dextranstripped serum, 2 mM glutamine, 0.1 mM NEAA, 1 mM Na-Pyruvate, 25 mMHepes) and incubated for 18 hrs at 37° C. in 5% CO₂. Dose responsecurves (10-point) were generated in 10 mM Hepes, 0.1% Pluronic F127, inthe presence of Forskolin. Cells were treated with 0.5 μl compound inthe presence of 2 μM Forskolin for 4 hrs at 37° C. The FRET-basedβ-lactamase fluorescent substrate (LiveBLAzer™-FRET B/G Loading KitCC4-AM; Invitrogen) was prepared according to manufacturer's directions,and incubated with cells for 2 hrs at room temperature. Plates were readat Ex:410/Em:458 and Ex:410/Em:522, and the response ratio determined.Data was analyzed by non-linear regression to determine the EC50 forinhibition of Forskolin induced cAMP.

Specificity Over Other S1P Receptors

To assess compound specificity on other SIP receptors the following celllines were used: S1P₂ CRE-bla CHOK1, S1P₃-Gα15 NFAT-bla HEK293T(Invitrogen), S1P₄-bla TANGO U2OS (Invitrogen), S1P₅-bla TANGO U2OS(Invitrogen). The same assay set up for S1P₁ was used but withoutForskolin. S1P₄ and S1P₅ assays were performed in FreeStyle Expressionmedium (Invitrogen). S1P₅ cells were incubated for 48 hrs in prior totreatment with compound.

Reported S1P₁ Activity

Activity data for selected S1P₁ agonists is displayed in Table 2. Theactivity range is denoted as follows: ++++ denotes agonist activity<0.05 nM. +++ denotes agonist activity between 0.05 to 0.50 nM, and ++denotes agonist activity between 0.50-5.00 nM, and + denotes agonistactivity >5.00 nM. N/A denotes not available.

TABLE 2 COMPOUND S1P₁ NUMBER ACTIVITY 1 +++ 2 +++ 3 ++ 4 ++ 5 ++ 6 ++ 7++++ 8 +++ 9 +++ 10 +++ 11 +++ 12 ++ 13 ++ 14 +++ 15 +++ 16 ++ 17 +++ 18++ 19 ++ 20 ++ 21 ++ 22 +++ 23 ++ 24 ++ 25 +++ 26 +++ 27 +++ 28 +++ 29+++ 30 ++ 31 +++ 32 ++++ 33 +++ 34 +++ 35 +++ 36 +++ 37 ++ 38 ++ 39 +++40 +++ 41 ++++ 42 +++ 43 +++ 44 ++++ 45 +++ 46 +++ 47 ++++ 48 ++++ 49 ++50 +++ 51 +++ 52 +++ 53 ++ 54 +++ 55 ++ 56 +++ 57 ++ 58 +++ 59 ++ 60 ++61 +++ 62 ++ 63 ++ 64 ++ 65 +++ 66 +++ 67 ++ 68 +++ 69 +++ 70 ++ 71 ++72 ++ 73 +++ 74 +++ 75 +++ 76 ++ 77 +++ 78 ++ 79 +++ 80 +++ 81 ++ 82 ++83 + 84 + 85 + 86 + 87 +++ 88 ++ 89 ++ 90 ++ 91 ++ 92 ++ 93 ++ 94 ++ 95++ 96 +++ 97 +++ 98 ++ 99 ++ 100 +++ 101 + 102 +++ 103 +++ 104 ++ 105 +106 + 107 ++ 108 + 109 ++ 110 ++ 111 +++ 112 +++ 113 +++ 114 +++ 115 +++116 ++ 117 +++ 118 +++ 119 +++ 120 ++ 121 ++ 122 ++ 123 ++ 124 ++ 125 ++126 ++ 127 ++ 128 + 129 + 130 ++ 131 ++ 132 ++ 133 ++ 134 ++ 135 + 136 +137 + 138 + 139 + 140 + 141 ++ 142 ++ 143 ++ 144 ++ 145 + 146 ++ 147 ++148 ++ 149 ++ 150 ++ 151 + 152 + 153 + 154 +++ 155 ++ 156 +++ 157 +++158 ++++ 159 +++ 160 ++++ 161 +++ 162 +++ 163 +++ 164 +++ 165 ++ 166 +++167 +++ 168 +++ 169 ++ 170 ++ 171 +++ 172 +++ 173 ++ 174 +++ 175 ++ 176++ 177 +++ 178 +++ 179 ++ 180 + 181 + 182 ++ 183 ++ 184 + 185 + 186 +++187 ++ 188 ++ 189 + 190 ++ 191 + 192 + 193 + 194 ++ 195 ++ 196 ++ 197 ++198 +++ 199 +++ 200 +++ 201 +++ 202 ++ 203 ++ 204 ++ 205 ++ 206 +++ 207++ 208 ++ 209 ++ 210 ++ 211 ++ 212 + 213 ++ 214 ++ 215 ++ 216 ++ 217 +218 + 219 +++ 220 +++ 221 +++ 222 + 223 ++ 224 + 225 + 226 ++ 227 +

S1P₁-S1P₅ data for specific compounds is presented in Table 3. Theagonist values (EC₅₀) are reported in nM.

TABLE 3 COMPOUND NUMBER S1P₁ S1P₂ S1P₃ S1P₄ S1P₅ 430.07 >10000 >10000 >10000 444 46 0.25 >10000 >10000 2171 194 470.03 >10000 >10000 >10000 22 56 0.32 >10000 >10000 >10000 139 580.29 >10000 >10000 >10000 47 166 0.14 8448 >10000 743 64 1720.19 >10000 >10000 >10000 203 186 0.41 >10000 >10000 >10000 126

In Vivo Assays Determination of Absolute Oral Bioavailability in Rats.

All pharmacokinetic studies were conducted in non-fasted femaleSprague-Dawely rats (Simonsen Laboratories or Harlan Laboratories). Ratswere housed in an ALAAC accredited facility and the research wasapproved by the facilities Institutional Animal Care and Use Committee(IACUC). The animals were acclimated to the laboratory for at least 48 hprior to initiation of experiments.

Compounds were formulated in 5% DMSO/5% Tween20 and 90% purified water(intravenous infusion) or 5% DMSO/5% Tween20 and 90% 0.1N HCL (oralgavage). Depending upon the solubility properties of the compound,alternate oral formulations were used (e.g. 0.5%carboxymethylcellulose). The concentration of the dosing solutions wasverified by HPLC-UV. For intravenous dosing, compounds were administeredby an infusion pump into the jugular vein over one minute to manuallyrestrained animals (n=4 rats/compound). Oral dosing was by gavage usinga standard stainless steel gavage needle (n=2-4 rats/compound). For bothroutes of administration, blood was collected at eight time-points afterdosing with the final sample drawn 24 h post dose. Aliquots of the bloodand/or plasma samples were transferred to polypropylene 96-well plateand frozen at −20° C. until analysis.

After thawing the blood and/or plasma samples at room temperature, 5 μLof DMSO was added to each well. Proteins were precipitated by adding 150μL acetonitrile containing 200 nM internal standard(4-hydroxy-3-(alpha-iminobenzyl)-1-methyl-6-phenylpyrindin-2-(1H)-one)and 0.1% formic acid. Plates were mixed for 1 min on a plate shaker tofacilitate protein precipitation and then centrifuged at 3,000 rpm for10 min to pellet protein. The supernatant was transferred to a cleanplate and centrifuged at 3,000 rpm for 10 min to pellet any remainingsolid material prior to LC/MS/MS analysis. Calibration curve standardswere prepared by spiking 54 compound stock in DMSO into freshlycollected EDTA rat blood. An eight point standard curve spanning a rangeof 5 nM to 10,000 nM was included with each bio-analytical run. Thestandards were processed identically to the rat pharmacokinetic samples.

Concentrations in the rat pharmacokinetic samples were determined usinga standardized HPLC-LC/MS/MS method relative to the eight point standardcurve. The system consisted of a Leap CTC Pal injector, Agilent 1200HPLC with binary pump coupled with an Applied Biosystems 3200 QTrap.Compounds were chromatographed on a Phenomenex Synergy Fusion RP 20×2 mm2 um Mercury Cartridge with Security Guard. A gradient method was usedwith mobile phase A consisting of 0.1% formic acid in water and mobilephase B consisting of 0.1% formic acid in acetonitrile at flow ratesvarying from 0.7 to 0.8 mL/min. Ions were generated in positiveionization mode using an electrospray ionization (ESI) interface.Multiple reaction monitoring (MRM) methods were developed specific toeach compound. The heated nebulizer was set at 325° C. with a nebulizercurrent of 4.8 μA. Collision energies used to generate daughter ionsranged between 29 and 39 V. Peak area ratios obtained from MRM of themass transitions specific for each compound were used forquantification. The limit of quantification of the method was typically5 nM. Data were collected and analyzed using Analyst software version1.4.2.

Blood and/or plasma concentration versus time data were analyzed usingnon-compartmental methods (WinNonlin version 5.2; model 200 for oraldosing and model 202 for intravenous infusion). Absolute oralbioavailability (%) was calculated using the following expression: (OralAUC×IV Dose)/(IV AUC×Oral Dose)×100.

Lymphopenia

In mice: Female C57BL6 mice (Simonsen Laboratories, Gilroy Calif.) werehoused in an ALAAC accredited facility and the research was approved bythe facilities Institutional Animal Care and Use Committee (IACUC). Theanimals were acclimated to the laboratory for at least 5 days prior toinitiation of experiments. Mice (n=3/compound/time-point) were dosed byoral gavage with 1 mg/kg compound formulated in a vehicle consisting of5% DMSO/5% Tween 20 and 90% 0.1N HCl. Control mice were dosed PO withthe vehicle. Terminal whole blood samples were collected from isofluraneanesthetized mice by cardiac puncture into EDTA. Whole blood wasincubated with rat anti-mouse CD16/CD32 (Mouse BD Fc Block, #553141),PE-Rat anti-mouse CD45R/B220 (BD #553089), APC-Cy7-Rat anti-mouse CD8a(BD #557654), and Alexa Fluor647-Rat anti-mouse CD4 (BD #557681) for 30min on ice. Red blood cells were lysed using BD Pharm Lyse Lysing buffer(#555899) and white blood cells were analyzed by FACS. Lymphopenia wasexpressed as the % of white blood cells that were CD4 or CD8 positive Tcells. The overall lymphopenia response over 24 h was estimated bycalculating the area under the effect curve (AUEC) using the lineartrapezoidal rule.

In rats: Female rats (Simonsen Laboratories, Gilroy Calif.) were housedin an ALAAC accredited facility and the research was approved by thefacilities Institutional Animal Care and Use Committee (IACUC). Theanimals were acclimated to the laboratory for at least 5 days prior toinitiation of experiments. Rats (n=3/compound/time-point) were dosed byoral gavage with 1 mg/kg compound formulated in a vehicle consisting of5% DMSO/5% Tween 20 and 90% 0.1N HCL. Control rats were dosed PO withthe vehicle. Whole blood was collected from isoflurane anesthetized ratsvia the retro-orbital sinus and terminal samples were collected bycardiac puncture into EDTA. Whole blood was incubated with mouseanti-rat CD32 (BD #550271), PE-mouse anti-rat CD45R/B220 (BD #554881),PECy5-mouse anti-rat CD4 (BD #554839), and APC-mouse anti-rat CD8a(eBioscience #17-0084) for 30 minutes on ice. Red blood cells were lysedusing BD Pharm Lyse Lysing buffer (#555899) and white blood cells wereanalyzed with a BD FACSArray. Lymphopenia was expressed as the % ofwhite blood cells that were CD4 or CD8 positive T cells. The overalllymphopenia response over 24 h was estimated by calculating the areaunder the effect curve (AUEC) using the linear trapezoidal rule. In someexperiments, total lymphocyte counts were determined using a standardimpediance based veterinary hematology analyzer (IDEXX PreclinicalResearch Services, Sacramento, Calif.).

Rat lymphopenia data for specific compounds is presented in Table 4. Thepercentage of lymphopenia at 24 h after a 0.2 mg/kg single dose regimentis reported. The estimated dose needed to produce 50% lymphopenia (ED₅₀)at 24 h after a 3-5 day dosing regimen is also reported. N/A is notavailable.

TABLE 4 Compound % Lymphopenia after ED₅₀ Number 24 h (0.2 mg/kg)(mg/kg) 43 40 N/A 46 39 N/A 47 17 N/A 56 52 N/A 58 49 N/A 166 47 0.07172 22 0.20 186 25 0.20

Evaluation of Therapeutic Index in Rats

Studies may be conducted in non-fasted male and female Sprague-Dawelyrats (Simonsen Laboratories). Rats may be housed in an AAALAC accreditedfacility and the research can be approved by the facilitiesInstitutional Animal Care and Use Committee (IACUC). The animals shouldbe acclimated to the laboratory for at least 5 days prior to initiationof experiments.

The compounds may be formulated as suspensions in a vehicle consistingof 0.5% carboxymethyl cellulose (Acros Organics) in purified water (pHadjusted to ˜2.2 with hydrochloric acid). The same formulation is usedin the rat lymphopenia and toxicology studies described below. Theconcentration of each compound in suspension should be verified to bewithin ±10% of the target concentration by HPLC-UV.

Prior to the conduct of toxicology studies, the effect of three to fivedaily doses of each compound on peripheral T-cell counts of female ratsmay be determined (see lymphopenia measurements in rats above). In theselymphopenia studies, blood samples are collected onto EDTA at intervalsafter the final study dose. The collection times need not be identicalfor each study, however, all studies may include a sample collected 24hours after the final dose. The lymphopenia data is used as a biomarkerto select equally pharmacologically active doses for the subsequenttoxicology study. The low dose for the toxicology study is the dose ofeach compound that resulted in a 50% reduction of T-cell count 24 hafter the final dose in the lymphopenia study relative to vehicletreated rats.

In the toxicology studies, three male and three female rats per groupare assigned to dosing groups using body weight based randomization. Acontrol group in each study receives vehicle. All animals are dosedorally by gavage on 5 or 14-consecutive days at a dose volume of 5mL/kg/day. The animals are observed daily for any manifestations ofadverse effect. Twenty-four hours after the final study dose, the ratsare anesthetized with isoflurane and a terminal blood sample is taken byintra-cardiac puncture for hematology and clinical chemistry evaluation(IDEXX Laboratories, Sacramento, Calif.). The lungs with trachea arecollected, weighed, and then prepared for histology by perfusion with10% neutral buffered formalin via the trachea. The internally fixedlungs are then preserved in 10% neutral buffered formalin and submittedfor histological examination (IDEXX).

The dose of each compound resulting in a 10% increase in the lung toterminal body weight ratio can be estimated for each compound by linearinterpolation. The therapeutic index can then be estimated as the ratioof the dose producing 10% lung weight increase to the dose producing 50%T-Cell depletion.

Description of the TNBS Crohn's Colitis Model in Rats

Male Sprague-Dawley rats (180-200 g) are acclimatized for seven days andthen assigned to 8 rats per group so that each group has approximatelythe same mean weight. Twenty-four hours prior to disease initiation,rats are deprived of food. Rats are anaesthetized and weighed, then 80mg/kg TNBS solution (50% TNBS: 50% 200 proof ethanol) is instilled intocolon via a 20 g feeding needle inserted into the anus. The rats aremaintained in head down position until recovery from anesthesia. Dailyoral dosing is initiated 2 h post TNBS-instillation for six days.Prednisolone serves as a positive control and is administered orallydaily at 10 mg/kg. Body weights are monitored daily and 24 h after thelast dose, all groups are terminated. The colon is removed, flushed offecal matter and examined for gross changes including strictures,adhesions and ulcers. The colon length, weight of the distal 2 cm, andwall thickness is recorded.

Description of Influenza A H1N1 Model in Mice

Male C57B1/6 (6-8 weeks of age) may be acclimatized for seven days andthen assigned to 5-8 mice per group so that each group has approximatelythe same mean weight. Mice may be infected with 10⁴ PFUs mouse-adaptedinfluenza A virus (A/WSN/33) via the intra-tracheal route. Mice may thenbe treated with 0.2-1.5 mg/kg compound p.o. 1 hr post-infection. Fortyeight hours after infection mice may be euthanized by cervicaldislocation and bronchoalveolar lavage fluid can be collected.Quantitative cytokine analysis may be performed via ELISA. In someexperiments whole body perfusion can be performed and lungs can becollected for cellular enumeration of inflammatory cells. Longevitystudies may be performed by infection with 3-10×10⁴ PFUs mouse-adaptedinfluenza A virus over 14 days.

1-61. (canceled)
 62. A method for the synthesis of a compound comprisingan indane moiety having a chiral carbon in the five-membered ring of theindane moiety where the compound is enantiomerically enriched withrespect to the chiral carbon, the method comprising the steps of (i)providing a compound comprising an indane moiety where the ring carbonof the five-membered ring of the indane moiety where chiral substitutionis desired is oxo substituted at such carbon, and wherein a carbon ofthe phenyl ring is halo substituted; (ii) reacting such compound with achiral reagent selected from the group consisting of a Corey BakshitaShibata-oxazaborolidine and a chiral sulfinamide of the form RS(═O)NH₂where R is selected from the group consisting of t-butyl, branched C₂₋₆alkyl and C₃₋₈ cycloalkyl; and (iii) forming the chiral center at theindane moiety carbon previously bound to the oxo group by eitherreacting such compound with a suitable reducing agent along with thechiral reagent in step (ii) or reacting the result of the reaction ofsuch compound with a suitable reducing agent.
 63. The method of claim 62wherein the chiral reagent is the Corey BakshitaShibata-oxazaborolidine.
 64. The method of claim 62 wherein the chiralreagent is (R)-(−)-(2)-methyl-CBS-oxazaborolidine or(S)-(−)-(2)-methyl-CBS-oxazaborolidine.
 65. The method of claim 63wherein the compound comprising an indane moiety provided in step (i) iscontacted with the chiral reagent to form in step (iii) Formula VI-R orVI-S:

wherein Z is Cl, Br or I.
 66. The method of claim 65 wherein the methodfurther comprises the step of protecting the hydroxy group of FormulaVI-R or VI-S by treating Formula VI-R or VI-S with a protecting agent toform Formula VIa-R or VIa-S:

wherein PG is a protecting group.
 67. The method of claim 66 wherein theprotecting agent is TBSCl.
 68. The method of claim 66 wherein the methodfurther comprises the step of reacting Formula VIa-R or VIa-S withboronic acid or bis(pinacolato)diboron to form a boronic acid orboronate ester of Formula VIb-R or VIb-S:


69. The method of claim 62 wherein the chiral reagent is RS(═O)NH₂ andthe compound comprising an indane moiety is enantiomerically enrichedwith respect to a carbon-nitrogen bond on a ring carbon of thefive-membered ring of the indane moiety.
 70. The method of claim 69wherein the chiral reagent is t-Bu-S(═O)NH₂.
 71. The method of claim 69wherein the compound comprising an indane moiety provided in step (i) iscontacted with the chiral reagent to form in step (ii) Formula VII:

wherein Z is Cl, Br or I.
 72. The method of claim 69 wherein a compoundof Formula VIII-R or VIII-S is formed in step (iii):


73. The method of claim 72 wherein the method further comprises the stepof contacting Formula VIII-R or VIII-S with 1,4-dioxane in the presenceof an acid to form Formula VIb-R or VIb-S or Formula IX-R or IX-S:


74. The method of claim 73 wherein the method further comprises the stepof protecting the amino group by treating Formula IX-R or IX-S with aprotecting agent to form Formula IXa-R or IXa-S:


75. The method of claim 74 wherein the protecting agent isdi-tert-butyldicarbonate.
 76. The method of claim 74 wherein the methodfurther comprises the step of reacting Formula IXa-R or IXa-S withboronic acid or bis(pinacolato)diboron to form a boronic acid orboronate ester of Formula IXb-R or IXb-S:


77. The method of any one of claim 68 or 76 wherein the method furthercomprises the step of reacting Formula VIb-R, Formula VIb-S, FormulaIXb-R or Formula IXb-S with Formula XI to form Formula XII-R or XII-S:

to form Formula XII-R or XII-S:

wherein each A¹ and each A² is independently N, or CH; R¹ isdi-substituted phenyl or di-substituted pyridinyl where the phenyl andpyridinyl substituents are each independently selected from the groupconsisting of halo, nitro, cyano, perfluromethyl, fluorinated methyl,and C₁₋₄-alkoxy; provided that if R¹ is di-substituted phenyl, suchphenyl is para-substituted with C₁₋₄-alkoxy; and X is NH or O.
 78. Themethod of claim 77 wherein R¹ is di-substituted phenyl where the phenylsubstituents are F and Y, wherein Y is —CN, —Cl, or —CF₃.
 79. The methodof claim 78 wherein the method further comprises the step of reactingFormula XII-R or XII-S with iPrOH in the presence of NaOiPr to fromFormula XIII-R or XIII-S:


80. The method of claim 79 wherein the method further comprises the stepof deprotecting the hydroxyl group wherein X is O, or the amino groupwherein X is NH, by treating Formula XIII-R or XIII-S with adeprotecting agent.
 81. The method of claim 80 wherein the methodfurther comprises the step of converting the deprotected amino group toa secondary amine.
 82. The method of 78 wherein Y is CN.
 83. The methodof claim 78 wherein A¹ is N and A² is N.
 84. The method of claim 83wherein Formula XI is prepared following the process comprising the stepof a) treating a di-substituted benzaldehyde with potassium phosphatemonobasic to form a di-substituted benzoic acid; b) contacting thedi-substituted benzoic acid with H₂NNHCSNH₂ to form anamino-1,3-4-thiadizole having a di-substituted phenyl group substitutedon the thiadiazole moiety; and c) treating the amino-1,3-4-thiadizole instep b) with a mixture of copper bromide and isoamylnitrite.
 85. Themethod of claim 78 wherein A¹ is N and A² is CH.
 86. The method of claim85 wherein Formula XI is prepared following the process comprising thestep of a) contacting 2-bromothiazole with a (di-substitutedphenyl)boronic acid to form a 2-(di-substituted phenyl)thiazole; and b)treating the 2-(di-substituted phenyl)thiazole with NBS.
 87. The methodof claim 78 wherein A¹ is CH and A² is N.
 88. The method of claim 87wherein Formula XI is prepared following the process comprising the stepof a) contacting 5-(tributylstannyl)thiazole with an iodobenzene havingtwo other substituents to form a 5-(di-substituted phenyl)thiazole; andb) treating the 2-(di-substituted phenyl)thiazole with NBS. 89.(canceled)